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Review, Development

Porf-2 = Arhgap39 = Vilse: A Pivotal Role in Neurodevelopment, Learning and Memory

Felicia V. Nowak
eNeuro 14 September 2018, 5 (5) ENEURO.0082-18.2018; DOI: https://doi.org/10.1523/ENEURO.0082-18.2018
Felicia V. Nowak
Department of Biomedical Sciences, Diabetes Institute and Program in Molecular and Cellular Biology, Ohio University, Athens, OH 45701
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Abstract

Small GTP-converting enzymes, GTPases, are essential for the efficient completion of many physiological and developmental processes. They are regulated by GTPase activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs). Arhgap39, also known as preoptic regulatory factor-2 (Porf-2) or Vilse, a member of the Rho GAP group, was first identified in 1990 in the rat CNS. It has since been shown to regulate apoptosis, cell migration, neurogenesis, and cerebral and hippocampal dendritic spine morphology. It plays a pivotal role in neurodevelopment and learning and memory. Homologous or orthologous genes are found in more than 280 vertebrate and invertebrate species, suggesting preservation through evolution. Not surprisingly, loss of the Arhgap39/Porf-2 gene in mice manifests as an embryonic lethal condition. Although Arhgap39/Porf-2 is highly expressed in the brain, it is also widely distributed throughout the body, with potential additional roles in oncogenesis and morphogenesis. This review summarizes, for the first time, the known information about this gene under its various names, in addition to considering its transcripts and proteins. The majority of findings described have been made in rats, mice, humans, and fruit flies. This work surveys the known functions, functional mediators, variables modifying expression and upstream regulators of expression, and potential physiological and pathological roles of Arhgap39/Porf-2 in health and disease.

  • Apoptosis
  • Arhgap39
  • dendritic spines
  • learning and memory
  • Porf-2
  • RhoGAP

Significance Statement

This review comprehensively includes what is currently known about Arhgap39/Porf-2 under its multiple names. Arhgap39 is a critically required molecule for neurodevelopment, learning, and memory that is expressed throughout the lifespan. It also has definitive roles in stem cell fate and cell migration, apoptosis, and proliferation, in both neural and nonneural sites. Homologous or orthologous genes have been conserved for millennia through evolution with a wide phylogenetic distribution from invertebrates to mammals. Its expression is exquisitely regulated by age, sex, location, and hormones. The consequences of dysregulation of Arhgap39 are currently under investigation.

Introduction

GTP-converting enzymes and their modifying proteins

Small GTP-converting enzymes, GTPases, ranging in size from 20 to 40 KDa, are essential for the efficient completion of many physiologic and developmental processes (Peck et al., 2002; Moon and Zheng, 2003; Jiang and Ramachandran, 2006; Tcherkezian and Lamarche-Vane, 2007; De Filippis et al., 2014; Ghosh et al., 2017). The GTPases switch between an active GTP-bound state and an inactive GDP-bound form as illustrated in Fig. 1. These switches are mediated by GTPase activating (or accelerating) proteins (GAPs) and guanine nucleotide exchange factors (GEFs). GEFs promote the binding of GTP, thus favoring the active state, while GAPs enhance the intrinsic activity of the GTPase, leading to GTP hydrolysis and returning the GTPase to an inactive state. Thus, GAPs can also be considered co-effectors with their GTPase partners. The inactive state is further promoted by guanine nucleotide dissociation inhibitors (GDIs), which sequester and stabilize the GDP-associated form.

Figure 1.
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Figure 1.

Schematic of Rac/Rho functional conversion, activation, and inactivation. GAP, GTPase activating protein; GDI, guanine nucleotide dissociation inhibitor; GEF, guanine nucleotide exchange factor; GTPase, guanine nucleotide triphosphate hydrolase.

There are five GTPase subfamilies: Ras (rat sarcoma), Rho (Ras homolog), Rab (rat brain), Arf/Sar (ADP-ribosylation factor/secretion-associated Ras-related protein), and Ran (Ras-related nuclear) in eukaryotes. These five subfamilies have been extensively studied in yeast, Arabidopsis, rice, Drosophila melanogaster, and selected vertebrates, especially rodents and humans (Jiang and Ramachandran, 2006; De Filippis et al., 2014; Yorimitsu et al., 2014). They regulate a diverse array of cellular functions, such as cytoskeletal reorganization, cell motility and polarity, vesicular trafficking, and cell fate and differentiation. Each GTPase subfamily has an associated GAP subfamily. Several groups of Rho GTPases exist, including Rho, Rac, Cdc42, and Rnd. An individual RhoGAP can interact with several Rho GTPases, depending on the cellular and developmental context.

A brief history of Arhgap39/Porf-2 discovery

The first paper on Arhgap39/Porf-2 reported the partial sequence and tissue distribution of the messenger RNA in the rat (Nowak, 1990). Subsequently, the investigation of the physiology and regulation of Arhgap39/Porf-2 in the rat led to the publication of 11 peer-reviewed manuscripts, including a summary book chapter on the discovery and characterization of Porf-2 (Nowak, 2014). It was found that Arhgap39/Porf-2 proteins are encoded by multiple RNA transcripts with tissue-specific expression. Arhgap39/Porf-2 is highly expressed in mammalian brain, including hypothalamus (regulation of metabolism and reproduction) and hippocampus (essential for learning and memory; Nowak, 1990; Hu and Nowak, 1994). The pattern of hypothalamic expression in the preoptic area-anterior hypothalamus (POA-AH) during a critical period of prenatal development is sex specific, with levels peaking earlier in males [embryonic day 18 (E18)–E19] than in females [postnatal day 0 (P0); Nowak and Gore, 1999]. It was found that the hormones, estradiol (E2) and progesterone (P4), regulate its expression in the female rat brain (Nowak et al., 1999). In males, gonadotropic pituitary factors decrease Arhgap39/Porf-2 mRNA in the POA and in the testes (Nowak et al., 1997) and testicular factors decrease Arhgap39/Porf-2 mRNA in the POA, but not in the medial basal hypothalamus (MBH) or cerebral cortex. Through this work it was also learned that Arhgap39/Porf-2 is highly expressed in a subset of immature germ cells in testes (Nowak et al., 1997). In sum, these results suggest that precise regulation of Arhgap39/Porf-2 expression has an impact on both CNS development and reproductive health. Finally it was discovered, using Southern blot analysis, that Arhgap39/Porf-2-like genes were present in nine widely ranging groups of vertebrates including primates, ungulates, rodents, birds, and fish (Schmerr et al., 2002), but the functions of this gene remained elusive. For more detail, see Variables modifying expression and upstream regulators.

Arhgap39/Porf-2—from EST to ORF

Arhgap39/Porf-2, also known as Vilse, KIAA1688, D15Wsu169e, CrossGAP, and Rho GTPase activating protein39, is a RhoGAP protein. Its ortholog is known as Arhgap93B in Drosophila. Evidence that this gene contains a functional open reading frame (ORF) emerged slowly, initially based on a partial sequence (Nowak, 1990) from a rat brain cDNA library. Its existence was hinted at as a member of several expressed sequence tag (EST) collections (Ko et al., 1998; Miki et al., 2001; Okazaki et al., 2002), including pre-implantation mouse embryo (Ko et al., 2000), and orphan gene libraries (Bonaldo et al., 1996; Carninci et al., 2000). Arhgap39/Porf-2 has been identified in more than 20 large-scale comprehensive enumerations of genes expressed as RNA transcripts and proteins. The complete mouse coding sequence was predicted in 2001 (Kawai et al., 2001) and verified by Okazaki et al. (2004). The Arhgap39/Porf-2 story has emerged slowly from a series of studies that demonstrate regional, temporal, and physiologic variations in expression, tissue, and location, some of which likely reflect species-specific functional roles for this gene. These will be discussed in more detail below.

Gene, RNA, and Protein (Table 1)

Phylogenetic distribution of Arhgap39/Porf-2

In 2002, the first phylogenetic distribution analysis was reported for Arhgap39/Porf-2 (Schmerr et al., 2002). Southern blot analysis using a rat probe revealed homologs in human, mouse, pig, sheep, cow, chicken (two bands), and zebrafish. It was shown that, in the rat, Arhgap39/Porf-2 is a single-copy gene (Nowak et al., 1997), and this has been confirmed in human and mouse with the sequencing of their complete genomes. In Drosophila, there is a single ortholog. However, the possibility remains that duplications have occurred in other species, including chickens.

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Table 1.

Arhgap39/Porf-2 gene structure, RNA transcripts, and proteins

In 2002, the Mammalian Gene Collection Program team identified murine Arhgap39/Porf-2 as a candidate full-ORF clone (Strausberg et al., 2002). Subsequently, in 2004, the Mammalian Genome Project reported the full-ORF cDNA sequences in mouse and human (Gerhard et al., 2004). In 2011, the mouse gene location was determined by the Jackson Laboratory (Bar Harbor, ME) to be on chromosome 15 (Diez-Roux et al., 2011). The gene is positioned on chromosome 7 in rats and on chromosome 8 in humans.

To date, 180 orthologs, identified by gene and exome sequencing, have been reported in a variety of vertebrate species, from platypuses (https://www.ncbi.nlm.nih.gov/gene/103168041) to equids (Hestand et al., 2015) and penguins (https://www.ncbi.nlm.nih.gov/gene/103901269). Moreover, the homologous mouse and human genes are located in a large conserved syntenic region corresponding to human chromosome 8 and mouse chromosome 15, supporting derivation from a common ancestor that existed at minimum 75 million years ago (Mouse Genome Sequencing Consortium et al., 2002). A related gene (Arhgap93B) in Drosophila and other invertebrates has now been identified in >100 additional species. As the common ancestor of vertebrates and insects existed at minimum ∼530 million years ago, this raises the possibility that Arhgap39/Porf-2 is even older, but this idea remains to be rigorously evaluated.

DNA and RNA structure and modifications

The mouse Arhgap39/Porf-2 gene is ∼94,000 base pairs in length and contains 13 exons. The Rattus norvegicus gene is slightly shorter at ∼92,000 bp, also with 13 exons. The Homo sapiens gene is ∼171,000 bp with 16 exons. The arrangement and spacing of the 12 3′-most exons are similar in these three species; the increased length of the human gene appears to reflect extensions of the introns upstream of the fourth rat/mouse exon. Whereas the Drosophila counterpart is only 14,785 bp, it has 14 exons and 3 domains that are highly conserved within the vertebrate genes noted above; these are WW, myosin tail homology 4 (MyTH4), and GAP domains described below.

Through in silico and Northern blot analyses, as well as sequencing of full-length cDNAs in human, rat, and mouse, it has been clearly demonstrated that the Arhgap39/Porf-2 gene can give rise to multiple RNA transcripts (Nowak, 1990, 1997; Rietveld et al., 2014). Although it was briefly reported that there was a second related gene in the mouse (Lundström et al., 2004), it was subsequently shown to represent an alternative splice form of Arhgap39/Porf-2 mRNA. However, there is evidence that two of the major transcripts give rise to slightly different proteins, owing to alternative splicing of the in-frame exon 7 (Fig. 2). The mouse protein isoforms 1 and 2 differ by elimination of exon 7 in isoform 2, which results in a 31-amino-acid deletion in the MyTH4 domain. Human isoforms 1 and 2 are similar to mouse isoform 2 and the single verified rat isoform in that they all encode a protein that lacks exon 7. Human isoforms 1 and 2 differ in their 5′ untranslated regions. In addition to the verified transcripts, there are a number of predicted transcripts. To a large extent, the resulting protein or other products of these transcripts have not been characterized. Alternative splicing occurs in 41% of mouse transcriptome and, in transcripts which contain a coding sequence, 79% of splice variations alter the protein products, and potentially, their subcellular localization and function (Okazaki et al., 2002). It remains to be seen whether there are different forms of Arhgap39/Porf-2 protein in different subcellular compartments or with alternative posttranslational modifications that allow for it to have several separate functions.

Figure 2.
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Figure 2.

Sequences of two isoforms of Arhgap39/Porf-2 protein in mouse. The protein sequence numbers correspond to those in the NCBI database. Adapted from https://www.ncbi.nlm.nih.gov/gene/223666 (mouse). The functional domains include two WW, and one each of MyTH4 and GAP. Protein isoform 2 differs from isoform 1 in the deletion of 31 amino acids, encoded by exon 7, from the MyTH4 domain.

Protein domains and modifications

The RhoGAP family members are notable for having multiple functional domains in addition to the GAP domain, including many that have been implicated in protein–protein interactions. This organization may facilitate interactions with more than one signaling pathway (Moon and Zheng, 2003; Tcherkezian and Lamarche-Vane, 2007). In the mouse, as well as in Drosophila, Arhgap39/Porf-2 protein has been shown to have three potentially functional domain regions, as shown in Fig. 2.

Two WW domains

The first hypothesized functional region is represented by a pair of WW domains at the N terminus of the predicted Drosophila protein (Lundström et al., 2004) and mouse isoform 1 (Lim et al., 2014). WW domains are ∼35–45 amino acids in length and are characterized by the presence of hydrophobic amino acids with cyclic side chains, including tryptophan, tyrosine, phenylalanine, and proline, but do not usually otherwise exhibit significant homology between different genes. However, the two WW domains of human Arhgap39/Porf-2 exhibit 84% and 77% sequence similarity, respectively, with the related drosophila Arhgap93B (Lundström et al., 2004). WW domains recognize and interact with proline-rich segments of other proteins to facilitate protein–protein interactions (Otte et al., 2003).

MyTH4 domain

The second region is a MyTH4 domain, an ∼150-amino-acid module. MyTH4 domains have been identified as a conserved sequence in the tail domains of several different unconventional myosins and a plant kinesin-like microtubule protein. There is a 44% protein sequence similarity between the H. sapiens Arhgap39/Porf-2 and Drosophila Arhgap93B MyTH4 domains (Lundström et al., 2004). Although the function of MyTH4 domains is not yet fully understood, there is evidence that the MyTH4 domain of Myosin-X (Myo10) binds to microtubules (Kerber and Cheney, 2011). The MyTH4 domain has also been found in several nonmotor proteins. Interestingly, the results of Huang et al. (2002) suggest a possible role for one of these (MAX-1) in netrin-induced axon repulsion in Caenorhabditis elegans by modulating the UNC-5 receptor signaling pathway. MAX-1 homologues are also found in Drosophila, mouse, and human (Kikuno et al., 2000; Huang et al., 2002). An emerging theme is that many, and perhaps most, guidance cues are bifunctional. Arhgap39/Porf-2 and MAX-1 are both MyTH4 domain–containing proteins that display this attraction-repulsion dichotomy.

RhoGAP domain

The third functional region is a RhoGAP domain close to the C terminus. RhoGAP domains are ∼140 amino acids, sharing 20%–40% amino acid identity (Lamarche and Hall, 1994). The actual GTPases with which they interact cannot be predicted by the sequence but must be experimentally determined. The human Arhgap39/Porf-2 GAP domain shares 86.5% homology with the rat, 88.8% with the mouse (personal calculation), and 61% with Drosophila (Lundström, Gallio, 2004). The rat also has transcripts that include the RhoGAP domain; however, it also has at least two variants, X4 and X5, that lack this domain. Instead, each contains a distinct C-terminal sequence.

Additional motifs and modifications

In addition to the WW, MyTH4, and GAP domains, the predicted protein isoforms 1 and 2 have 19 potential motif sites, including 8 serine/threonine phosphorylation sites, 2 SH2, and a single SH3 motif (Obenauer et al., 2003). Serine or tyrosine phosphorylation of regulatory proteins including GAPs is one mechanism by which activation and subcellular location can be controlled. One example is CdGAP, a RhoGAP whose activity is regulated through phosphorylation by ERK (Tcherkezian et al., 2005). Another example is the phosphorylation of the RacGAP protein, FilGAP, at Ser-402 (Morishita et al., 2015). Phosphorylation increases its RacGAP activity in vivo and promotes diffuse distribution in the cytoplasm, which stimulates cell spreading on fibronectin. The total number and active sites of phosphorylation in the Arhgap39/Porf-2 protein have not been determined. One of the predicted phosphorylation sites in Arhgap39/Porf-2 at serine 169, within a casein kinase I motif, was confirmed by a screen of mouse synaptosomal proteins isolated from 2–5-month cortex (Munton et al., 2007). In addition, phospho-serine 589 was identified in a large screening of the developing mouse brain (E16.5) for phosphorylated peptides by Ballif et al. (2004); interestingly, this was not one of the phosphorylation sites previously predicted.

SH2 and SH3 are homology domains found in a family of oncogenic nonreceptor tyrosine kinases. An SH2 domain, which was first identified in the oncoproteins Src and Fujiyami poultry sarcoma, is ∼100 amino acid residues long. It functions as a regulatory module of intracellular signaling cascades by interacting with high affinity to phosphotyrosine-containing target peptides in a sequence-specific and strictly phosphorylation-dependent manner.

SH3 domains are small protein domains of ∼60 amino acid residues. SH3 domains are found in proteins of signaling pathways regulating the cytoskeleton, the Ras protein, the Src kinase, and many others. SH3 domains interact with other proteins and mediate assembly of specific protein complexes, typically via binding to proline-rich peptides in their respective binding partner.

The presence of these motifs that accelerate protein localization and interactions in Arhgap39/Porf-2 are consistent with its role as a RhoGAP that is involved in several complex signaling pathways.

Tissue distribution of Arhgap39/PORF-2 RNAs and proteins (Table 2)

The first partial Arhgap39 (Porf-2) sequence was reported in a cDNA library constructed with RNA isolated from adult rat hypothalamus (Nowak, 1990). This group detected multiple poly A–enriched RNA transcripts expressed widely in the adult rat, including cerebral cortex, hippocampus, hypothalamus, cerebellum, amygdala, anterior pituitary, adrenal, testis, liver, and kidney (Nowak, 1990, 1997, 2014). ESTs and alternative splicing sequence enriched tags (ASSETs; Watahiki et al., 2004) were also found in E7.5 mouse embryo placental growth cone (Ko et al., 1998) and E17.5 mouse skin and testes (Miki et al., 2001). In 2001, human KIAA1688 cDNA was sequenced, and human tissue distribution of Arhgap39/Porf-2 RNA was quantified by PCR (Kikuno et al., 2004). Although RNA levels were highest in brain and spinal cord, it was also found in testis, kidney, liver, pancreas, lung, and other tissues at lower levels.

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Table 2.

Tissue and cell type distribution of Arhgap39/Porf-2 expression in human, mouse, rat, and fruit fly

RNA transcripts have also been detected in human hypothalamus, adrenal, prostate, and placenta (Nowak, 2014) and in several cultured cell types, including human melanocytes (Watahiki et al., 2004), human vascular endothelial cells (Kaur et al., 2008), mouse cerebellar stem cells (C17.2; Ma and Nowak, 2011), Fisher rat thyroid-like (FRTL-5) cells, mouse hypothalamic neurons (GT-1; Nowak, 2014), and human pancreatic beta cells (Wang J., 2012, personal communication). Recently, several extensive studies of gene expression in human (Fagerberg et al., 2014), mouse (Yue et al., 2014), and rat (Yu et al., 2014) have expanded the molecular distribution of Arhgap39/Porf-2 RNA to include intestine, spleen, heart, thymus, uterus, lung, stomach, ovary, urinary bladder, mammary gland, prostate, salivary gland, thyroid gland, and adipose tissue.

Ballif et al. (2004) identified an Arhgap39/Porf-2 phosphopeptide in a large proteomic analysis of E16.5 mouse brain. Diez-Roux et al. (2011) found moderate protein expression of Arhgap39/Porf-2 (D15Wsu169e) in E14.5 mouse embryo brain and spinal cord and peripheral nervous system, and low expression in multiple other peripheral locations, including renal, hematopoietic, gastrointestinal, and smooth and striated muscle. Arhgap39/Porf-2 protein expression was also reported in mouse cerebellar stem cells (Ma and Nowak, 2011). Recently, several Arhgap39/Porf-2 proteins were detected in human male liver (unpublished observations, Liu, Zhang, Guo, and Nowak).

In the brain, Arhgap39/Porf-2 RNA was first localized to neurons (Nowak et al., 1999) in 60-d-old female rat hypothalamus by in situ hybridization analysis. It was later detected as a phosphoprotein by liquid chromatography-tandem mass spectrometry in synaptic terminals isolated from 2–5-month C57Bl/6 mouse cortex (Munton et al., 2007). Arhgap39/Porf-2 is also detected in neurospheres derived from mouse hippocampus (Huang et al., 2016).

Functional roles and downstream effectors (Table 3)

Arhgap39/Porf-2 has been shown to function through regulation of two Rho GTPases, Rac1 and Cdc42. Several investigators have shown that Arhgap39/Porf-2 is a regulator of Rho GTPases and as such plays a role in endothelial cell migration (Kaur et al., 2008), ganglion and axon tracking (Lundström et al., 2004; Hu et al., 2005), neural stem cell fate (Ma and Nowak, 2011; Huang et al., 2016), and dendritic spine formation (Lim et al., 2014; Lee et al., 2017). These studies further link Arhgap39/Porf-2 to angiogenesis, tracheal innervation, and CNS development.

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Table 3.

Functions and mediators of Arhgap39/Porf-2

Axon directional migration

Lundström et al. (2004) were the first to show a functional role for Arhgap93B, the Drosophila ortholog of Arhgap39/Porf-2. They demonstrated that the WW domains of Vilse, as they termed it, bind to the CC2 domain of the Slit receptor, Roundabout (Robo), and inactivate RacGTP to mediate Slit-directed midline repulsion of CNS axons in tracheal cells. They further demonstrated that both Drosophila Arhgap93B and human Arhgap39/Porf-2 GAP domains effectively stimulated GTP hydrolysis of Rac1. Soon thereafter, Hu et al. (2005) identified Vilse, which they called CrossGAP, as a regulator of midline axonal repulsive guidance in Drosophila. They confirmed the direct interaction between Vilse and Robo and the inactivation of Rac1 by Vilse. Interestingly, either too little or too much Vilse resulted in defective Robo-mediated, Slit-directed axon repulsion at the midline.

Endothelial cell migration

In human vascular endothelial cells, Arhgap39/Porf-2/Vilse is sequestered by Robo1 and Robo4, resulting in an increase in activated Cdc42. Cdc42-GTP then activates insulin receptor protein 53 (IRSp53) by binding to its CRIB domain. This exposes an SH3 domain that binds to Mena, an IRSp53 effector and mediates actin nucleation, resulting in filopodia formation and endothelial cell directional migration (Kaur et al., 2008).

Neural stem cell fate

In 2011, the roles of Arhgap39/Porf-2 in the mouse neural stem cell (NSC) line, C17.2, were discovered, including its negative effects on cell cycle and proliferation and potentiating effects on apoptosis. The key cell signaling components involved in mediating these effects were identified (Ma and Nowak, 2011). These include increased levels of p21 leading to cell cycle arrest and decreased cell proliferation, and enhanced drug-induced apoptosis through both p53-dependent and -independent pathways by upregulating Bcl-2 associated X protein (BAX). These findings are consistent with those of others who have shown that BAX and p53 are regulators of programmed cell death in mouse cerebellum (Geng et al., 2010) as well as with the finding that upregulation of BAX and p53 can suppress the growth of tumors, including gliomas (Zhen et al., 2017).

This work also demonstrated that Arhgap39/Porf-2 had no effect on NSC differentiation induced by serum starvation (Ma and Nowak, 2011). Although this study did not identify the GTPase substrate involved, Ras, Rho, and Cdc42 have all been shown to regulate cell cycle entry and cell proliferation (Olson et al., 1995; Olson et al., 1998; Welsh et al., 2001) and to determine the fate of NSCs by influencing the balance of stem cell maintenance with proliferation and apoptosis (Joseph and Hermanson, 2010). Other RhoGAPs including DLC2 (Ching et al., 2003) and tGAP1 (Modarressi et al., 2004) have been shown to decrease cell proliferation by slowing down the cell cycle. tGAP1 also induces apoptosis when overexpressed in somatic cells.

Huang et al. (2016) showed that the effects of Arhgap39/Porf-2 on cell proliferation of NSCs were mediated through its GAP domain. They extended previous in vitro findings in C17 cells that Arhgap39/Porf-2 is anti-proliferative (Ma and Nowak 2011) and demonstrated that Arhgap39/Porf-2 decreases proliferation in neurospheres from newborn mouse hippocampus as well as in hippocampal sections from 6-week-old mice (Huang et al., 2016). Transfection with a full-length Arhgap39/Porf-2 construct, but not one lacking the GAP domain, resulted in decreased levels of intranuclear β-catenin. The authors postulated that the observed effects on cell proliferation are mediated through the GAP domain, causing decreased translocation of β-catenin into the nucleus.

Dendritic spine morphology

Lim et al. (2014) demonstrated that Arhgap39/Porf-2 is required for normal dendritic spine formation in the rat dentate gyrus, a portion of the hippocampal formation, and in mouse neuroblastoma × rat glioma hybrid cells. Interaction of a proline motif in the neuron scaffold protein connector enhancer of kinase suppressor of ras2 (CNK2) with the WW domain of Vilse regulates Arhgap39/Porf-2 localization. This critical interaction maintains the RacGDP/GTP balance required for dendritic spine formation. It is of note that CNK2 has been implicated in X-linked cognitive impairment in a human subject (Houge et al., 2012). Additionally, constitutive lack of the RhoGAP, oligophrenin 1, in mice results in decreased density and increased length of dendritic spines in the amygdala (Khelfaoui et al., 2014) and failure of hippocampal CA1 dendritic spines to mature during development (Khelfaoui et al., 2007). These mice also display deficits in learning and memory as measured with Y-maze, O-maze, Morris water maze, and conditioned fear extinction, as well as altered hippocampal LTP. Deficits in mice of additional Rho GTPase regulators, including SRGAP3, BCR and ABR, ARG, ABL, Integrin 3α, KALRN, and ARGEF6, have also been associated with cognitive and anxiety-related behavioral alterations, such as decreases in novel object recognition and Y-maze alternation and social interactions, altered synaptic plasticity, and abnormal dendritic spine morphology (De Filippis et al., 2014). Finally, exome sequencing of individuals from a family with late-onset Parkinson’s disease identified a mutation (p.Arg667Gln) in Arhgap39/Porf-2 as a rare variant possibly associated with the disease (Schulte et al., 2014), indicating that dysregulation of this gene may also play a role in neurodegeneration.

Learning and memory

In 2014, Arhgap39/Porf-2 was among the genes identified to be associated with cognitive performance in humans (Rietveld et al., 2014). This may reflect variation in expression of mRNA variants 1 and 2, an interesting observation, since they both encode the same protein isoform, but differ in the 5′ UTR. Quite recently, Lee et al. (2017) described the effects in hippocampus of a widespread Arhgap39/Porf-2 knockout in mouse forebrain under the direction of the CamKII promoter. These mice show behavioral deficits in learning and memory as measured by Morris water maze and Y-maze performance. They also exhibit abnormal hippocampal signaling and dendritic spine morphology. Not surprisingly, given its high level of expression in placental growth cone and developing nervous system, a global constitutive knockout resulted in embryonic lethality, with incomplete embryo development.

Taken together, these findings indicate that Arhgap39/Porf-2 is an integral part of the signaling machinery that regulates hippocampal structure and function and more broadly neuronal function, through its effects on neuronal cell proliferation and apoptosis, its regulation of axonal migration, and its role in dendritic spine morphology, synaptic plasticity, and cognitive performance.

Oncogenesis

More recently, several bioinformatics analyses have uncovered associations of Arhgap39/Porf-2 mutations or variations in copy number or expression level with several types of cancer (https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=ARHGAP39, http://useast.ensembl.org/Homo_sapiens/Gene/Variation_Gene/Table?db=core;g=ENSG00000147799;r=8:144529179-144605816). These include tumors of the CNS, skin, prostate, and gastrointestinal tract; one conserved variant has been shown to correlate with prostate tumors and sarcomas in a family lineage (Jones, 2017). Given its roles in apoptosis and proliferation and interactions with p53 and BAX, a mutation that decreased expression of Arhgap39/Porf-2 could result in increased cell proliferation, leading to tumorigenesis.

Variables modifying expression and upstream regulators of Arhgap39/PORF-2 (Table 4)

Whereas it is important to know the downstream effects of Arhgap39/Porf-2 action, it is also critical to understand the physiologic factors that regulate Arhgap39/Porf-2 expression. It has been known for some time that Arhgap39/Porf-2 mRNA in the rat brain is localized mainly to neurons (Nowak et al., 1999) and that in the rat, age, sex differences, brain region, gonadal steroids, and developmental stage regulate/influence the expression of Arhgap39/Porf-2 mRNAs in hippocampus, hypothalamus, and cerebral cortex (Hu and Nowak, 1994, 1995; Nowak, 1997; Nowak and Gore, 1999; Nowak et al., 1999).

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Table 4.

Variables modifying expression and upstream regulators of Arhgap39/Porf-2

Developmental and age-related changes in CNS expression of Arhgap39/Porf-2

As measured by nuclease protection assays of cytoplasmic RNA, Arhgap39/Porf-2 RNA averages 40 μg/g total RNA from 15 d to 2 months of age in the male rat hippocampus. The levels increase more than 2-fold at 6 and 12 months, then decline with age. Why Arhgap39/Porf-2 is highest in the male rat hippocampus at middle age remains an unsolved question. Prenatal Arhgap39/Porf-2 RNA levels in the POA are high at E18–E19, then fall gradually until P15. This is followed by a plateau through 2 months of age when postnatal levels are highest (19.9 μg/g) followed by a progressive decrease with age (Hu and Nowak, 1994). Postnatal age-related changes in expression have also been identified in the MBH and cerebral cortex (Hu and Nowak, 1995), where Arhgap39/Porf-2 RNA is severalfold higher in both male and female rats at 15 d compared to 30 and 60 d, followed by a long plateau through 24 months of age. Arhgap39/Porf-2 RNA in the MBH also declines rapidly by 2-fold from E18–E19 to P15 in both sexes (Nowak and Gore, 1999). Its regionally distinctive, developmentally modified neuronal expression suggested early on that Arhgap39/Porf-2 has a critical role in prenatal and postnatal CNS development and function.

Sex differences in the developing CNS

There are also sex differences in Arhgap39/Porf-2 cytoplasmic RNA levels during development in the rat, being higher in male than in female hippocampus and MBH at P15 (Hu and Nowak, 1995). In the POA, late embryonic levels are higher in males at E18–E19, then decline rapidly, resulting in lower levels in males at P0 and P15 (Nowak and Gore, 1999). Thus there is a sex difference in timing for peak levels of Arhgap39/Porf-2 in the developing rat fetal POA, a brain region that is critical for normal feedback regulation of gonadotropin-releasing and -inhibiting hormones and reproductive function more generally.

Gonadal hormones

In the adult rat, Arhgap39/Porf-2 expression is responsive to extrinsic variations in circulating gonadal hormones in both females and males. In females ovariectomized at 44 days, treatment with E2 alone results in an increased level of Arhgap39/Porf-2 RNA in the POA and hippocampus compared with placebo-treated controls (Nowak et al., 1999). Replacement of only P4 upregulates Arhgap39/Porf-2 in POA and cerebral cortex. Treatment with E2 plus P4 also increases Arhgap39/Porf-2 in the hippocampus, but this combination decreases the RNA in POA and cortex. No changes are observed in the MBH. Thus the response of the female rat brain to gonadal steroids is highly region dependent. Based on Northern blot analysis of Arhgap39/Porf-2 mRNA in male rats subjected to hypophysectomy or castration, both pituitary and testicular factors directly or indirectly affect alternative splicing of Arhgap39/Porf-2 mRNA transcripts in the POA, MBH, and cerebral cortex (Nowak, 1997). At the present time, it is not known how this specifically impacts sex-related gene function or how Arhgap39/Porf-2 mediates the effects of reproductive axis hormones in the brain.

Pituitary factors

Expression of Arhgap39/Porf-2 RNA in rat testes is predominantly localized to spermatogonia and primary spermatocytes and is regulated by age and by pituitary gonadotrophic hormones (Nowak et al., 1997). Arhgap39/Porf-2 testicular expression declines with age in the rat (Nowak et al., 1997; Yu et al., 2014). At 60 d of age, Arhgap39/Porf-2 RNA has declined to 40% of the level at 15 d; there is a further 50% decline between 60 d and 6–12 months. By 24 months, the level is 8%–28% of that at 15 d. Hypophysectomy of young adult male rats results in a significant increase in testicular Arhgap39/Porf-2 to levels normally seen at 15 d. Although the developmental pattern of expression, in addition to the germ cell location and regulation by hormones of reproduction, suggests a function for Arhgap39/Porf-2 proteins in mammalian testes, that specific function is currently unknown. Another RhoGAP, tGAP1, which is mainly found in testes, has been shown to be expressed later, in round spermatids, where it slows down the cell cycle and may induce apoptosis (Modarressi et al., 2004).

Epigenetic mechanisms

Recently, epigenetic mechanisms have been implicated in the regulation of Arhgap39/Porf-2 expression (https://ccb-web.cs.uni-saarland.de/mirtargetlink/network.php?type=Target_Gene&qval=ARHGAP39). miRTargetLink currently lists 23 miRNAs with weaker experimental evidence that may target Arhgap39/Porf-2.

Metabolism, insulin, and IGF-1

More recently, it was discovered that Arhgap39/Porf-2 expression is also modified by two important regulators of metabolism and growth, insulin and IGF-1 (Wang, 2011). Both insulin and IGF-1 decrease Arhgap39/Porf-2 expression in FRTL-5 cells in a dose- and time-dependent manner. That this downregulation is signaled through the PI-3-kinase/AKT and Raf kinase/MEK pathways was shown by use of specific chemical inhibitors, including wortmannin and Ly29402 for PI-3-K and Akt inhibitor-4, Raf kinase inhibitor, and high-dose wortmannin and PD98059 for MEK/Erk phosphorylation. Additionally, knockdown of IGF-1 receptor (IGF-1R) and possibly insulin receptor results in a partial reversal of the downregulation. An additional study of interest (Bentov et al., 2014) showed an association of IGF-1R deficiency in aged dermal fibroblasts with decreased Erk phosphorylation and decreased cell proliferation. Although Arhgap39/Porf-2 is expressed in skin and is a potential mediator of this effect, neither it nor other potential downstream regulators were measured in this study.

It makes physiologic sense that stimulators of growth and metabolism would act counter to Arhgap39/Porf-2, a regulator that promotes apoptosis and inhibits cell proliferation. Recent findings have shown that neurogenesis is impaired and apoptosis increases in hippocampi of subjects with diabetes (Ho et al., 2013). A logical question that follows is, what happens to endogenous levels of Arhgap39/Porf-2 when insulin or IGF-1 is deficient as in type 1 diabetes or growth hormone deficiency, either congenital (Laron syndrome) or age-related (Gong et al., 2014), or if the response to insulin or IGF-1 is blocked, as seen in obesity with insulin resistance, type 2 diabetes, or aging (Bentov et al., 2014)?

Insulin resistance and obesity

Two recent findings suggest a link between insulin resistance and Arhgap39/Porf-2. In a Zucker rat model of obesity-related diabetes, treatment with an antioxidant-fortified diet resulted in partial preservation of glomerular filtration rate in 20-wk-old diabetic females (Slyvka et al., 2009). This group also found decreased expression of Arhgap39/Porf-2 RNA in the kidney compared to diabetic females on a control diet. Obese humans and rodents also have been shown to have decreased hepatic expression of Arhgap39/Porf-2 and carcinoembryonic antigen related cell adhesion molecule 1 (Heinrich et al., 2017). Decreased carcinoembryonic antigen related cell adhesion molecule 1 leads to a decrease in insulin clearance, exacerbating hyperinsulinemia. Thus the decrease in Arhgap39/Porf-2 could be a result of increased suppression by insulin in the prediabetic state, although later, as insulin resistance with hyperinsulinemia advances to frank diabetes, Arhgap39/Porf-2 levels can be anticipated to rise. Both insulin and IGF-1 deficiencies have been linked to neurodegenerative (Biessels et al., 2014; Ekblad et al., 2017) and cardiovascular (Higashi et al., 2013) disease. This, in conjunction with the above findings, raises the question of whether increased Arhgap39/Porf-2 expression factors into the pathophysiology of diabetic complications more generally.

Potential physiologic and pathophysiological roles of Arhgap39/Porf-2

Tables 5 and 6 summarize the potential physiologic and pathophysiological roles of Arhgap39/Porf-2, based on the findings to date. Its wide phylogenetic and tissue distribution, its complex physiologic regulation, and its pivotal role in basic cell functions support the expectation that there is much more to discover about this particular RhoGAP.

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Table 5.

Potential physiologic roles of Arhgap39/Porf-2

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Table 6.

Potential pathophysiological roles of Arhgap39/Porf-2

Summary

Arhgap39/Porf-2 (Vilse, CrossGAP) is a Rho GTPase activating protein that interacts with Rac1 and Cdc42. As is the case with many RhoGAPs, it has multiple functions. Among these are inhibition of cell proliferation, promotion of apoptosis, regulation of axon guidance and endothelial cell migration, and development of normal dendritic spine morphology in the hippocampus, which may underlie support of normal learning and memory. Various physiologic and hormonal cues direct region-specific expression in the brain, suggesting that day-to-day expression is carefully monitored and maintained. Finally, the finding that deletion of Arhgap39/Porf-2 is fatal and the fact that this gene has been conserved through evolution for millennia highlight the crucial importance of this gene.

Acknowledgments

Acknowledgments: The author acknowledges her colleagues, Pat O’Connor, PhD, and Yuriy Slyvka, MD/PhD, for helpful suggestions and insightful comments. Many thanks as well to the students and collaborators who have contributed to the work in the author’s lab on the regulation and function of Arhgap39/Porf-2: Shuang Ma, PhD, Zhenchao Wang, MD/PhD, Jose Torres, MS, Shuang-Bao Hu, PhD, Jennifer Yee, DO, Shannon Gilham, DO, Kimberly Nemeth, DO, Ekokobe Fonkem, DO, Matthew Colpo, Jill Carlsen, Wenjuan Zhang, Christopher Pun, Andrea Gore, PhD, Jennifer Golden, MS, Gonzalo Torres, PhD, and Xinhao Liu, MD/PhD.

Footnotes

  • The author declares no competing financial interests.

  • Funding Source: Ohio University Faculty Fellowship Award.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

References

  1. ↵
    Ballif BA, Villén J, Beausoleil SA, Schwartz D, Gygi SP (2004) Phosphoproteomic analysis of the developing mouse brain. Mol Cell Proteomics 3:1093–1101. doi:10.1074/mcp.M400085-MCP200 pmid:15345747
    OpenUrlAbstract/FREE Full Text
  2. ↵
    Bentov I, Damodarasamy M, Plymate S, Reed MJ (2014) Decreased proliferative capacity of aged dermal fibroblasts in a three dimensional matrix is associated with reduced IGF1R expression and activation. Biogerontol 15:329–337. doi:10.1007/s10522-014-9501-8
    OpenUrlCrossRefPubMed
  3. ↵
    Biessels GJ, Strachan MW, Visseren FL, Kappelle LJ, Whitmer RA (2014) Dementia and cognitive decline in type 2 diabetes and prediabetic stages: towards targeted interventions. Lancet Diabetes Endocrinol 2:246–255. doi:10.1016/S2213-8587(13)70088-3 pmid:24622755
  4. ↵
    Bonaldo MF, Lennon G, Soares MB (1996) Normalization and subtraction: two approaches to facilitate gene discovery. Genome Res 6:791–806. pmid:8889548
    OpenUrlAbstract/FREE Full Text
  5. ↵
    Carninci P, Shibata Y, Hayatsu N, Sugahara Y, Shibata K, Itoh M, Konno H, Okazaki Y, Muramatsu M, Hayashizaki Y (2000) Normalization and subtraction of cap-trapper-selected cDNAs to prepare full-length cDNA libraries for rapid discovery of new genes. Genome Res 10:1617–1630. pmid:11042159
    OpenUrlAbstract/FREE Full Text
  6. ↵
    Ching YP, Wong CM, Chan SF, Leung TH, Ng DC, Jin DY, Ng IO (2003) Deleted in liver cancer (DLC) 2 encodes a RhoGAP protein with growth suppressor function and is underexpressed in hepatocellular carcinoma. J Biol Chem 278:10824–10830. doi:10.1074/jbc.M208310200 pmid:12531887
    OpenUrlAbstract/FREE Full Text
  7. ↵
    De Filippis B, Romano E, Laviola G (2014) Aberrant Rho GTPases signaling and cognitive dysfunction: in vivo evidence for a compelling molecular relationship. Neurosci Biobehav Rev 46: 285–301. doi:10.1016/j.neubiorev.2014.06.007
    OpenUrlCrossRefPubMed
  8. ↵
    Diez-Roux G, Banfi S, Sultan M, Geffers L, Anand S, Rozado D, Magen A, Canidio E, Pagani M, Peluso I, Lin-Marq N, Koch M, Bilio M, Cantiello I, Verde R, et al. (2011) A high-resolution anatomical atlas of the transcriptome in the mouse embryo. PLoS Biol 9:e1000582. doi:10.1371/journal.pbio.1000582 pmid:21267068
    OpenUrlCrossRefPubMed
  9. ↵
    Ekblad LL, Rinne JO, Puukka P, Laine H, Ahtiluoto S, Sulkava R, Vitanen M, Jula A (2017) Insulin resistance predicts cognitive decline: an 11-year follow-up of a nationally representative adult population sample. Diabetes Care 40:751–758. doi:10.2337/dc16-2001
    OpenUrlAbstract/FREE Full Text
  10. ↵
    Fagerberg L, Halström BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J, Habuka M, Tahmasebpoor S, Danielsson A, Edlund K, Asplund A, Sjöstedt E, Lundberg E, Szigyarto CA, Skogs M, et al. (2014) Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteom 13:397–406. doi:10.1074/mcp.M113.035600
    OpenUrlAbstract/FREE Full Text
  11. ↵
    Geng Y, Walls KC, Ghosh AP, Akhtar RS, Klocke BJ, Roth KA (2010) Cytoplasmic p53 and activated Bax regulate p53-dependent, transcription-independent neural precursor cell apoptosis. J Histochem Cytochem 58:265–275. doi:10.1369/jhc.2009.954024 pmid:19901272
    OpenUrlCrossRefPubMed
  12. ↵
    Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, et al. (2004) The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res 14:2121–2127. doi:10.1101/gr.2596504 pmid:15489334
  13. ↵
    Ghosh P, Rangamani P, Kufareva I (2017) The GAPs, GEFs, GDIs and now GEMs: new kids on the heterotrimeric G protein signaling block. Cell Cycle 16:607–612. doi:10.1080/15384101.2017.1282584 pmid:28287365
    OpenUrlCrossRefPubMed
  14. ↵
    Gong Z, Kennedy O, Sun H, Wu Y, Williams GA, Klein L, Cardoso L, Matheny RW, Jr., Hubbard GB, Ikeno Y, Farrar RP, Schaffler MB, Adamo ML, Muzumdar RH, Yakar S (2014) Reductions in serum IGF-1 during aging impair health span. Aging Cell 13:408–418. doi:10.1111/acel.12188 pmid:24341939
    OpenUrlCrossRefPubMed
  15. ↵
    Heinrich G, Muturi HT, Rezaei K, Al-Share QY, DeAngelis AM, Bowman TA, Ghadieh HE, Ghanem SS, Zhang D, Garofalo RS, Yin L, Najjar SM (2017) Reduced hepatic carcinoembryonic antigen-related cell adhesion molecule 1 level in obesity. Front Endocrinol 8:54–58. doi:10.3389/fendo.2017.00054 pmid:28396653
    OpenUrlCrossRefPubMed
  16. ↵
    Hestand MS, Kalbfleisch TS, Coleman SJ, Zeng Z, Liu J, Orlando L, MacLeod JN (2015) Annotation of the protein coding regions of the equine genome. PloS One 10:e0124375. doi:10.1371/journal.pone.0124375 pmid:26107351
    OpenUrlCrossRefPubMed
  17. ↵
    Higashi Y, Sukhanov S, Anwar A, Shai SY, Delafontaine P (2013) Aging, atherosclerosis, and IGF-1. J Gerontol Series A, Biol Sci Med Sci 67:626–639. doi:10.1093/gerona/gls102 pmid:22491965
    OpenUrlCrossRefPubMed
  18. ↵
    Ho N, Sommers MS, Lucki I (2013) Effects of diabetes on hippocampal neurogenesis: links to cognition and depression. Neurosci Biobehav Rev 37:1346–1362. doi:10.1016/j.neubiorev.2013.03.010 pmid:23680701
    OpenUrlCrossRefPubMed
  19. ↵
    Houge G, Rasmussen IH, Hovland R (2012) Loss-of-function CNKSR2 mutation is a likely cause of non-syndromic X-linked intellectual disability. Mol Syndromol 2:60–63. pmid:000335159 pmid:22511892
  20. ↵
    Hu H, Li M, Labrador JP, McEwen J, Lai EC, Goodman CS, Bashaw GJ (2005) Cross GTPase-activating protein (CrossGAP)/Vilse links the Roundabout receptor to Rac to regulate midline repulsion. Proc Natl Acad Sci U S A 102:4613–4618. doi:10.1073/pnas.0409325102 pmid:15755809
    OpenUrlAbstract/FREE Full Text
  21. ↵
    Hu SB, Nowak FV (1994) Regional distinction in age-related changes of preoptic regulatory factor-1 and preoptic regulatory factor-2 mRNA expression in the rat brain. Mol Cell Neurosci 5:376–381. doi:10.1006/mcne.1994.1045 pmid:7804608
    OpenUrlCrossRefPubMed
  22. ↵
    Hu SB, Nowak FV (1995) Sex-specific changes in preoptic regulatory factor-1 and preoptic regulatory factor-2 mRNA expression in the rat brain during development. Endocrine 3:421–424. doi:10.1007/BF02935647 pmid:21153245
    OpenUrlCrossRefPubMed
  23. ↵
    Huang GH, Yang XT, Chen K, Xing J, Guo L, Zhu L, Li HJ, Li XC, Zhang SY, Feng DF (2016) Porf-2 inhibits neural stem cell proliferation through Wnt/beta-catenin pathway by its GAP domain. Front Cell Neurosci 10:85–97. doi:10.3389/fncel.2016.00085 pmid:27064446
    OpenUrlCrossRefPubMed
  24. ↵
    Huang X, Cheng HJ, Tessier-Lavigne M, Jin Y (2002) MAX-1, a novel PH/MyTH4/FERM domain cytoplasmic protein implicated in netrin-mediated axon repulsion. Neuron 34:563–76. pmid:12062040
    OpenUrlCrossRefPubMed
  25. ↵
    Jiang SY, Ramachandran S (2006) Comparative and evolutionary analysis of genes encoding small GTPases and their activating proteins in eukaryotic genomes. Physiol Genomics 24:235–251. doi:10.1152/physiolgenomics.00210.2005 pmid:16332933
    OpenUrlCrossRefPubMed
  26. ↵
    Jones, RM. (2017) Identification of novel risk variants for sarcoma and other cancers by whole exome sequencing in cancer cluster families. PhD Thesis, The University of Western Australia. Available at http://research-repository.uwa.edu.au/files/21715375/thesis_doctor_of_philosophy_jones_Rachel_Maree_2017.pdf.
  27. ↵
    Joseph B, Hermanson O (2010) Molecular control of brain size: regulators of neural stem cell life, death and beyond. Exp Cell Res 316:1415–1421. doi:10.1016/j.yexcr.2010.03.012 pmid:20307536
    OpenUrlCrossRefPubMed
  28. ↵
    Kaur S, Samant GV, Pramanik K, Loscombe PW, Pendrak ML, Roberts DD, Ramchandran R (2008) Silencing of directional migration in roundabout4 knockdown endothelial cells. BMC Cell Biol 9:61–72. doi:10.1186/1471-2121-9-61 pmid:18980679
    OpenUrlCrossRefPubMed
  29. ↵
    Kawai J, Shinagawa A, Shibata K, Yoshino M, Itoh M, Ishii Y, Arakawa T, Hara A, Fukunishi Y, Konno H, Adachi J, Fukuda S, Aizawa K, Izawa M, Nishi J, et al. (2001) Functional annotation of a full-length mouse cDNA collection. Nature 409:685–690. doi:10.1038/35055500 pmid:11217851
    OpenUrlCrossRefPubMed
  30. ↵
    Kerber ML, Cheney RE (2011) Myosin-X: a MyTH-FERM myosin at the tips of filopodia. J Cell Sci 124:3733–3741. doi:10.1242/jcs.023549 pmid:22124140
    OpenUrlAbstract/FREE Full Text
  31. ↵
    Khelfaoui M, Denis C, van Galen E, de Bock F, Schmitt A, Houbron C, Morice E, Giros B, Ramakers G, Fagni L, Chelly J, Nosten-Bertrand M, Billuart P (2007) Loss of X-linked mental retardation gene oligophrenin1 in mice impairs spatial memory and leads to ventricular enlargement and dendritic spine immaturity. J Neurosci 27:9439–9450. doi:10.1523/JNEUROSCI.2029-07.2007 pmid:17728457
    OpenUrlAbstract/FREE Full Text
  32. ↵
    Khelfaoui M, Gambino F, Houbaert X, Ragazzon B, Müller C, Carta M, Lanore F, Srikumar BN, Gastrein P, Lepleux M, Zhang CL, Kneib M, Poulain B, Reibel-Foisset S, Vitale N, Chelly J, Billuart P, Lüthi A, Humeau Y (2014) Lack of the presynaptic RhoGAP protein oligophrenin1 leads to cognitive disabilities through dysregulation of the cAMP/PKA signalling pathway. Phil Trans R Soc B 369:20130160. doi:10.1098/rstb.2013.0160 pmid:24298161
    OpenUrlCrossRefPubMed
  33. ↵
    Kikuno R, Nagase T, Nakayama M, Koga H, Okazaki N, Nakajima D, Ohara O (2004) HUGE: a database for human KIAA proteins, a 2004 update integrating HUGEppi and ROUGE. Nucleic Acids Res 32:D502–504. doi:10.1093/nar/gkh035 pmid:14681467
    OpenUrlCrossRefPubMed
  34. ↵
    Kikuno R, Nagase T, Waki M, Ohara O (2000) HUGE: a database for human large proteins identified in the Kasuza cDNA sequencing project. Nucl Acids Res 28:331–332. doi:10.1093/nar/28.1.331
    OpenUrlCrossRefPubMed
  35. ↵
    Ko MS, Kitchen JR, Wang X, Threat TA, Wang X, Hasegawa A, Sun T, Grahovae MJ, Kargul GJ, Lim MK, Cui Y, Sano Y, Tanaka T, Liang Y, Mason S, et al. (2000) Large-scale cDNA analysis reveals phased gene expression patterns during preimplantation mouse development. Development 127:1737–1749.
  36. ↵
    Ko MS, Threat TA, Wang X, Horton JH, Cui Y, Wang X, Pryor E, Paris J, Wells-Smith J, Kitchen JR, Rowe LB, Eppig J, Satoh T, Brant L, Fujiwara H, Yotsumoto S, Nakashima H (1998) Genome-wide mapping of unselected transcripts from extraembryonic tissue of 7.5-day mouse embryos reveals enrichment in the t-complex and under-representation on the X chromosome. Hum Mol Genet 7:1967–1978. pmid:9811942
    OpenUrlCrossRefPubMed
  37. ↵
    Lamarche N, Hall A (1994) GAPs for rho-related GTPases. Trends Genet 10:436–40. pmid:7871593
    OpenUrlCrossRefPubMed
  38. ↵
    Lee JY, Lee LJ, Fan CC, Chang HC, Shih HA, Min MY, Chang MS (2017) Important roles of Vilse in dendritic architecture and synaptic plasticity. Sci Rep 7:45646. doi:10.1038/srep45646 pmid:28368047
    OpenUrlCrossRefPubMed
  39. ↵
    Lim J, Ritt DA, Zhou M, Morrison DK (2014) The CNK2 scaffold interacts with vilse and modulates Rac cycling during spine morphogenesis in hippocampal neurons. Curr Biol 24:786–792. doi:10.1016/j.cub.2014.02.036 pmid:24656827
    OpenUrlCrossRefPubMed
  40. ↵
    Lundström A, Gallio M, Englund C, Steneberg P, Hemphälä J, Aspenström P, Keleman K, Falileeva L, Dickson BJ, Samakovlis C (2004) Vilse, a conserved Rac/Cdc42 GAP mediating Robo repulsion in tracheal cells and axons. Genes Dev 18:2161–2171. doi:10.1101/gad.310204 pmid:15342493
  41. ↵
    Ma S, Nowak FV (2011) The RhoGAP domain-containing protein, Porf-2, inhibits proliferation and enhances apoptosis in neural stem cells. Mol Cell Neurosci 46:573–582. doi:10.1016/j.mcn.2010.12.008 pmid:21185940
    OpenUrlCrossRefPubMed
  42. ↵
    Miki R, Kadota K, Bono H, Mizuno Y, Tomaru Y, Carninci P, Itoh M, Shibata K, Kawai J, Konno H, Watanabe S, Sato K, Tokusumi Y, Kikuchi N, Ishii Y, et al. (2001) Delineating developmental and metabolic pathways in vivo by expression profiling using the RIKEN set of 18,816 full-length enriched mouse cDNA arrays. Proc Natl Acad Sci U S A 98:2199–2204. doi:10.1073/pnas.041605498 pmid:11226216
    OpenUrlAbstract/FREE Full Text
  43. ↵
    Modarressi MH, Cheng M, Tarnasky HA, Lamarche-Vane N, de Rooij DG, Ruan Y, van der Hoorn FA (2004) A novel testicular RhoGAP-domain protein induces apoptosis. Biol Reprod 71:1980–1990. doi:10.1095/biolreprod.104.032805 pmid:15306557
    OpenUrlAbstract/FREE Full Text
  44. ↵
    Moon SY, Zheng Y (2003) Rho GTPase-activating proteins in cell regulation. Trends Cell Biol 13:13–22. pmid:12480336
    OpenUrlCrossRefPubMed
  45. ↵
    Morishita Y, Tsutsumi K, Ohta Y (2015) Phosphorylation of serine 402 regulates RacGAP protein activity of FilGAP protein. J Biol Chem 290:26328–26338. doi:10.1074/jbc.M115.666875 pmid:26359494
    OpenUrlAbstract/FREE Full Text
  46. ↵
    Mouse Genome Sequencing Consortium, Waterston RH, et al. (2002) Initial sequencing and comparative analysis of the mouse genome. Nature 420:520–562. doi:10.1038/nature01262 pmid:12466850
    OpenUrlCrossRefPubMed
  47. ↵
    Munton RP, Tweedie-Cullen R, Livingstone-Zatchej M, Weinandy F, Waidelich M, Longo D, Gehrig P, Potthast F, Rutishauser D, Gerrits B, Panse C, Schlapbach R, Mansuy IM (2007) Qualitative and quantitative analyses of protein phosphorylation in naive and stimulated mouse synaptosomal preparations. Mol Cell Proteomics 6:283–293. doi:10.1074/mcp.M600046-MCP200 pmid:17114649
    OpenUrlAbstract/FREE Full Text
  48. ↵
    Nowak FV (1990) Cloning of two hypothalamic cDNAs encoding tissue-specific transcripts in the preoptic area and testis. Mol Endocrinol 4:1205–1210. doi:10.1210/mend-4-8-1205 pmid:2293025
    OpenUrlCrossRefPubMed
  49. ↵
    Nowak FV (1997) Modulation of preoptic regulatory factor-2 (porf-2) mRNAs by castration and hypophysectomy. Endocrine 6:57–63. doi:10.1007/BF02738803 pmid:9225117
    OpenUrlCrossRefPubMed
  50. ↵
    Nowak FV (2014) Preoptic regulatory factor-2, a Rhogap domain protein that modifies cell cycle progression and apoptosis in the CNS. In: Stem Cells and Cancer Stem Cells, Vol 12 (Hayat MA, editor). New York: Springer Nature, pp. 219–230.
    OpenUrl
  51. ↵
    Nowak FV, Gore AC (1999) Perinatal developmental changes in expression of the neuropeptide genes preoptic regulatory factor-1 and factor-2, neuropeptide Y and GnRH in rat hypothalamus. J Neuroendocrinol 11:951–958. pmid:10583730
    OpenUrlCrossRefPubMed
  52. ↵
    Nowak FV, Torres G, Golden J, Hu SB (1997) Expression of the preoptic regulatory factor-1 and -2 genes in rat testis. Developmental and hormonal regulation. Endocrine 6:65–72. doi:10.1007/BF02738804 pmid:9225118
    OpenUrlCrossRefPubMed
  53. ↵
    Nowak FV, Torres GE, Hu SB (1999) Differential gene expression response to gonadal hormones by preoptic regulatory factors-1 and -2 in the female rat brain. Neuroendocrinology 69:191–201. doi:10.1159/000054418 pmid:10087451
    OpenUrlCrossRefPubMed
  54. ↵
    Obenauer JC, Cantley LC, Yaffe MB (2003) Scansite 2.0: Proteome-wide prediction of cell signaling interactions using short sequence motifs. Nucleic Acids Res 31:3635–3641. pmid:12824383
    OpenUrlCrossRefPubMed
  55. ↵
    Okazaki N, Kikuno RF, Ohara R, Inamoto S, Koseki H, Hiraoka S, Saga Y, Seino S, Nishimura M, Kaisho T, Hoshino K, Kitamura H, Nagase T, Ohara O, Koga H (2004) Prediction of the coding sequences of mouse homologues of KIAA gene: IV. The complete nucleotide sequences of 500 mouse KIAA-homologous cDNAs identified by screening of terminal sequences of cDNA clones randomly sampled from size-fractionated libraries. DNA Res 11:205–218. doi:10.1093/dnares/11.3.205
    OpenUrlCrossRefPubMed
  56. ↵
    Okazaki Y, Furuno M, Kasukawa T, Adachi J, Bono H, Kondo S, Nikaido I, Osato N, Saito R, Suzuki H, Yamanaka I, Kiyosawa H, Yagi K, Tomaru Y, Hasegawa Y, et al. (2002) Analysis of the mouse transcriptome based on functional annotation of 60,770 full-length cDNAs. Nature 420:563–573. doi:10.1038/nature01266 pmid:12466851
    OpenUrlCrossRefPubMed
  57. ↵
    Olson MF, Ashworth A, Hall A (1995) An essential role for Rho, Rac, and Cdc42 GTPases in cell cycle progression through G1. Science 269:1270–1272. pmid:7652575
    OpenUrlAbstract/FREE Full Text
  58. ↵
    Olson MF, Paterson HF, Marshall CJ (1998) Signals from Ras and Rho GTPases interact to regulate expression of p21Waf1/Cip1. Nature 394:295–299. doi:10.1038/28425 pmid:9685162
    OpenUrlCrossRefPubMed
  59. ↵
    Otte L, Wiedemann U, Schlegel B, Pires JR, Beyermann M, Schmieder P, Krause G, Volkmer-Engert R, Schneider-Mergener J, Oschkinat H (2003) WW domain sequence activity relationships identified using ligand recognition propensities of 42 WW domains. Protein Sci 12:491–500. doi:10.1110/ps.0233203 pmid:12592019
    OpenUrlCrossRefPubMed
  60. ↵
    Peck J, Douglas G, Wu CH, Burbelo PD (2002) Human RhoGAP domain-containing proteins: structure, function and evolutionary relationships. FEBS Lett 528:27–34. doi:10.1016/S0014-5793(02)03331-8
    OpenUrlCrossRefPubMed
  61. ↵
    Rietveld CA, Esko T, Davies G, Pers TH, Turley P, Benyamin B, Chabris CF, Emilsson V, Johnson AD, Lee JJ, de Leeuw C, Marioni RE, Medland SE, Miller MB, Rostapshova O, et al. (2014) Common genetic variants associated with cognitive performance identified using the proxy-phenotype method. Proc Natl Acad Sci U S A 111:13790–13794. doi:10.1073/pnas.1404623111
    OpenUrlAbstract/FREE Full Text
  62. ↵
    Schmerr MS, Schleter DS, Pate M, Nowak FV (2002) Phylogenetic distribution of the preoptic regulatory factor genes. 84th Annual Meeting of the Endocrine Society. Bethesda, MD: The Endocrine Society Press, p. 353.
  63. ↵
    Schulte EC, Ellwanger DC, Dihanich D, Manzoni C, Stangl K, Schormair B, Graf E, Eck S, Mollenhauer B, Haubenberger D, Pirker W, Zimprich A, Brücke T, Lichtner P, Peters A, et al. (2014) Rare variants in LRRK1 and Parkinson’s Disease. Neurogenetics 15:49–57. doi:10.1007/s10048-013-0383-8 pmid:24241507
    OpenUrlCrossRefPubMed
  64. ↵
    Slyvka Y, Inman SR, Malgor R, Jackson EJ, Yee J, Oshogwemoh O, Adame J, Nowak FV (2009) Protective effects of antioxidant-fortified diet on renal function and metabolic profile in obese Zucker rat. Endocrine 35:89–100. doi:10.1007/s12020-008-9121-7 pmid:19051067
    OpenUrlCrossRefPubMed
  65. ↵
    Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF, Zeeberg B, Buetow KH, Schaefer CF, Bhat NK, Hopkins RF, et al. (2002) Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proc Natl Acad Sci U S A 99:16899–16903. doi:10.1073/pnas.242603899 pmid:12477932
  66. ↵
    Tcherkezian J, Danek EI, Jenna S, Triki I, Lamarche-Vane N (2005) Extracellular signal-regulated kinase 1 interacts with and phosphorylates CdGAP at an important regulatory site. Mol Cell Biol 25:6314–6329. doi:10.1128/MCB.25.15.6314-6329.2005 pmid:16024771
    OpenUrlAbstract/FREE Full Text
  67. ↵
    Tcherkezian J, Lamarche-Vane N (2007) Current knowledge of the large RhoGAP family of proteins. Biol Cell 99:67–86. doi:10.1042/BC20060086 pmid:17222083
    OpenUrlCrossRefPubMed
  68. ↵
    Wang Z. (2011) Role of growth factors on Porf-2 expression. Dissertation. Athens, OH: Ohio University.
  69. ↵
    Watahiki A, Waki K, Hayatsu N, Shiraki T, Kondo S, Nakamura M, Sasaki D, Arakawa T, Kawai J, Harbers M, Hayashizaki Y, Carninci P (2004) Libraries enriched for alternatively spliced exons reveal splicing patterns in melanocytes and melanomas. Nat Methods 1:233–239. doi:10.1038/nmeth719
    OpenUrlCrossRefPubMed
  70. ↵
    Welsh CF, Roovers K, Villanueva J, Liu Y, Schwartz MA, Assoian RK (2001) Timing of cyclin D1 expression within G1 phase is controlled by Rho. Nat Cell Biol 3:950–957. doi:10.1038/ncb1101-950 pmid:11715015
    OpenUrlCrossRefPubMed
  71. ↵
    Yorimitsu T, Sato K, Takeuchi M (2014) Molecular mechanisms of Sar/Arf GTPases in vesicular trafficking in yeast and plants. Front Plant Sci 5:411–422. doi:10.3389/fpls.2014.00411 pmid:25191334
    OpenUrlCrossRefPubMed
  72. ↵
    Yu Y, Fuscoe JC, Zhao C, Guo C, Jia M, Qing T, Bannon DI, Lancashire L, Bao W, Du T, Luo H, Su Z, Jones WD, Moland CL, Branham WS, et al. (2014) A rat RNA-Seq transcriptomic BodyMap across 11 organs and 4 developmental stages. Nat Commun 5:3230. doi:10.1038/ncomms4230 pmid:24510058
    OpenUrlCrossRefPubMed
  73. ↵
    Yue F, Cheng Y, Breschi A, Vierstra J, Wu W, Ryba T, Sandstrom R, Ma Z, Davis C, Pope BD, Shen Y, Pervouchine DD, Djebali S, Thurman RE, Kaul R, Rynes E, et al. (2014) A comparative encyclopedia of DNA elements in the mouse genome. Nature 515:355–64. doi:10.1038/nature13992 pmid:25409824
  74. ↵
    Zhen Z-G, Ren S-H, Ji H-M, Ma J-H, Ding X-M, Feng F-Q, Chen S-L, Zou P, Ren J-R, Jia L (2017) Linarin suppresses glioma through inhibition of NF-κB/p65 and up-regulating p53 expression in vitro and in vivo. Biomed Pharmacother 95:363–374. doi:10.1016/j.biopha.2017.08.023
    OpenUrlCrossRefPubMed

Synthesis

Reviewing Editor: Margaret McCarthy, Univ of Maryland School of Medicine

Decisions are customarily a result of the Reviewing Editor and the peer reviewers coming together and discussing their recommendations until a consensus is reached. When revisions are invited, a fact-based synthesis statement explaining their decision and outlining what is needed to prepare a revision will be listed below. The following reviewer(s) agreed to reveal their identity: Joshua Corbin, Nathalie Lamarche-Vane.

The authors present a comprehensive review of Arhgap39/Porf2/Vilse, a member of the Rho GTPase family, in a variety of biological functions. The review puts into perspective known information of this gene in a manner that is interesting and original. The review overall is well written and will provide a nice addition to the literature. Two reviewers provide a combination of suggestions for additional material and interpretations, as well as a number of specific editorial changes.

Overall comments/suggestions:

1) Both reviewers felt that Figure 1 is not all that informative. They suggested it be replaced with any of the following: a figure of Rac/Rho pathway and how Arhgap39 fits in this pathway, a figure of protein structure w/functional domains (referenced to Lines 146-211) and/or a figure with the structure of the protein modules and include the possible alternative splice variants.

2) The review focused on many aspects of Arhgap39/Porf2/Vilse, both neuronal and non-neuronal, thus the title maybe too specific.

3) Authors have not mentioned the tentative role of Arhgap39 in oncogenic processes (though this maybe getting too outside the theme of eNeuro). Arhgap39 is a gene involved in apoptosis and proliferation, related with the well-known tumor suppressor P53 and BAX, and several mutations has been reported in the Cosmic database associated to carcinogenesis. This information might be integrated in the text, as well as in table 6. Some of this information can be found at, for examples:

- http://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=ARHGAP39

- IPA reports (Qiagen)

http://useast.ensembl.org/Homo_sapiens/Gene/Variation_Gene/Table?db=core;g=ENSG00000147799;r=8:144529179-144605816

- http://research-repository.uwa.edu.au/files/21715375/THESIS_DOCTOR_OF_PHILOSOPHY_JONES_Rachel_Maree_2017.pdf

4) Authors may also want to mention a role in morphogenesis (observed in Lee et al., 2017) and to add 'Morphogenesis' also in table 5.

5) It may also be worth mentioning the following study on Parkinson's disease https://link.springer.com/content/pdf/10.1007%2Fs10048-013-0383-8.pdf

6) As a general criticism, throughout the text it is difficult to follow to what species some of the assessments refer. E.g. lines: 300, 337, 354, 362, 376 (expression of what -protein/gene- in which species?), 389... Please, clarify.

7) Another general criticism along the text, to better clarify whether expression refers to gene or protein expression, i.e. using italics for gene expression of Arhgap39 (e.g. line 12).

8) Title in section V and table 4 'Upstream regulators' may be modified by something like 'Variables modifying Arhgap39 expression and upstream regulators'. Since 'Age' or 'sex' can be seen not as upstream regulators, but more as variables or conditions affecting Arhgap39 expression.

MiRs should be mentioned in this section as proper upstream regulators.

For more information on miR targeting Arhgap39, please refer to:

- IPA reports (Qiagen). Information at the end of this page.

- miR databases e.g. https://ccb-web.cs.uni-saarland.de/mirtargetlink/network.php?type=Target_Gene&qval=ARHGAP39

Specific line by line comments:

Lines 36, 438: In the text 'millennia' is mentioned as synonym of preservation through evolution. However, most of the genes, even if not preserved through evolution, have been preserved for millennia. E.g. line 11 could be modified by : 'Homologous or orthologous genes arehave been found in over 280 vertebrate and invertebrate species, suggesting preservation along evolution'. E.g. line 36: It Homologous or orthologous genes have been conserved for millennia along evolution with a wide phylogenetic distribution from invertebrate to mammals.

Line 45: phrase unclear. Maybe more clear including a sentence similar to Lee et al., 2017: "Rho GTPases switch between an active GTP-bound form and an inactive GDP-bound state". They in turn are modified by This switch is mediated by GTPase activating proteins (GAPs) and....

Line 54: Arabaidopsis

Line 63: Over the next 15 years (from Novak 1990 to 2014= 24 years). Or to date?

line 69-70: the statement "hypothalamic expression during a critical period of prenatal development is sex-specific" should include more details (ei what stages, what regions, specific differences between sexes, etc)

Line 80: Birds or fishes are not species. An Arhgap39/Porf-2-like gene was present in nine widely ranging animal species of vertebrates? including primates, ungulates, rodents, birds and fishes.

lines 78-81: it is stated that Arhgap39 was present in 9 species, but on line 111 it is stated that there are 180 orthologs in a variety of species. The numbers need clarification as there appears to be a disconnect.

Line 83: suggested to include synomym 'Rho GTPase activating protein 39'.

Line 175 (example): Throughout the text some sentences lack references.

Line 230: Since 2014 is now a while ago, suggested to remove "quite"

Line 232: "sightings" is not the most appropriate word in this context perhaps change to "gene expression studies"

Line 237-238: Please be more specific about "certain ganglia"

Line 255: These findings studies.

Line 281: BAX and P53: suggested to mention their role in protection against cancer progression.

Line 295: unclear paragraph.

Line 300: Lim aet al. (or Lim and Ritt).

Line 313: It maybe worth to mention what kind of alterations

Line 339: The subheading regarding age is a bit confusing. Is this the changes in levels of expression over developmental and post natal time? What does the RNA levels represent-total tissue? Examined by which type of analysis (qPCR?)

Line 353: suggested to add "differences" after sex

Line 437: since the gene deletion is constitutive, suggested to remove "developmental"

Table 2: Lines on column 1 on Peripheral Nervous system and Endocrine Organs not aligned with corresponding column 2.

Table 3: If possible it would be informative to add citations next to each of the functions so the reader can easily refer back to the original work.

Last page in pdf, is another figure? It appears cut off.

Page 1, line 7: a member of the Rho GTPase-activating protein group

Page 2, line 45: replace "modified" by regulated

Page 3, line 46: remove "that direct the binding and dissociation of GTP and GDP with the GTPases": this is not accurate.

Page 3, line 48: remove "GAPs promote the binding of GDP": this is wrong. GAPs enhance the intrinsic GTPase activity, leading to GTP hydrolysis and the inactive state of the GTPase.

Page 3, line 51: There are five small GTPase subfamilies, not superfamilies.

Page 3, line 53: replace superfamilies by subfamilies.

Page 3,line 49: replace GDP by guanine nucleotide

Page 12, line 250: replace modification by regulation

Page 12, line 252: replace "an activator of" by a negative regulator of

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Porf-2 = Arhgap39 = Vilse: A Pivotal Role in Neurodevelopment, Learning and Memory
Felicia V. Nowak
eNeuro 14 September 2018, 5 (5) ENEURO.0082-18.2018; DOI: 10.1523/ENEURO.0082-18.2018

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Porf-2 = Arhgap39 = Vilse: A Pivotal Role in Neurodevelopment, Learning and Memory
Felicia V. Nowak
eNeuro 14 September 2018, 5 (5) ENEURO.0082-18.2018; DOI: 10.1523/ENEURO.0082-18.2018
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  • Article
    • Abstract
    • Significance Statement
    • Introduction
    • Gene, RNA, and Protein (Table 1)
    • Tissue distribution of Arhgap39/PORF-2 RNAs and proteins (Table 2)
    • Functional roles and downstream effectors (Table 3)
    • Variables modifying expression and upstream regulators of Arhgap39/PORF-2 (Table 4)
    • Summary
    • Acknowledgments
    • Footnotes
    • References
    • Synthesis
  • Figures & Data
  • Info & Metrics
  • eLetters
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Keywords

  • apoptosis
  • Arhgap39
  • Dendritic spines
  • learning and memory
  • Porf-2
  • RhoGAP

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