Genetic regulation of arealization of the neocortex
Introduction
The cerebral cortex, a brain component unique to mammals, arises from the dorsal telencephalon (dTel). The cerebral cortex is divided into regions, with the largest region, the neocortex positioned between two other regions, the archicortex (midline cortex and hippocampus) and paleocortex (olfactory piriform cortex). Among the many features that distinguish the neocortex from other regions is its laminar patterning into six major, radially organized, layers that are morphologically and connectionally distinct. In its tangential dimension, the neocortex is organized into ‘areas’ that are functionally unique subdivisions distinguished by differences in cytoarchitecture and chemoarchitecture, input and output connections, and patterns of gene expression.
Determining the mechanisms that control the development of cortical areas, a process termed arealization, is a major issue in neurobiology that has attracted the attention and imagination of many investigators, particularly in the past decade [1, 2, 3, 4, 5]. Proper area patterning of the neocortex is a crucial developmental event, because neocortical areas form the basis for sensory perception, control of our movements, and mediate our behavior. Many features must be properly specified during arealization — not only the unique properties that determine an area's function and interaction with other neural structures, but also the appropriate size.
The specification and differentiation of neocortical areas is controlled by an interplay between genetic regulation intrinsic to the neocortex — characterized by transcription factors (TFs) expressed by cortical progenitors and morphogens expressed by telencephalic patterning centers — and extrinsic influences such as thalamocortical axon (TCA) input that relays in an area-specific fashion sensory information from the principal sensory nuclei of dorsal thalamus to the primary cortical areas (Figure 1). Although of undeniable importance, surprisingly little is known about the mechanisms that control arealization, and most of what we know is recent. For instance, direct evidence for the intrinsic genetic control of the area identities of cortical progenitors was first reported early in this decade [6, 7]. Here we describe recent major findings most directly relevant to neocortical arealization, focusing on genetic regulation intrinsic to the neocortex. Findings in the past year have substantially expanded our understanding of this process, but at the same time they have called into question the precise role of some players.
Section snippets
Neocortex primer
The neocortex has four ‘primary’ areas; each is the cornerstone of clusters of functionally related areas that include scores of higher order areas that are prominently interconnected. Three of the primary areas are sensory: the primary visual (V1), somatosensory (S1), and auditory (A1) areas, which process primary information received from the eye/retina (vision), body (somatosensation), and inner ear/cochlea (audition), respectively. The fourth primary area is motor (M1), which controls
Telencephalic patterning centers in arealization
Arealization is controlled by a regulatory hierarchy beginning with morphogens secreted from patterning centers positioned at the perimeter of dTel, which establish within cortical progenitors the differential expression of TFs that determine their area identity and that inherited by their neuronal progeny that form the CP (Figure 1). Four telencephalic patterning centers appear to be involved directly or indirectly in cortical patterning, as well as in regionalization of the telencephalon
Commissural plate: an anterior patterning center
The anterior neural ridge (ANR), which is the anterior junction between neural and non-neural ectoderm, and later through morphogenesis becomes the CoP, formed by the fusion of the neural plate folds at the anterior margin of the forebrain, is an anterior patterning center for arealization (Figure 1) [22]. The ANR/CoP is prominently defined by the overlapping expression domains of Fgf8, Fgf17, and Fgf18. Of these, Fgf8, and to a lesser degree Fgf17, have been most studied in arealization. They
Cortical hem: a dorsal/caudal patterning center
The cortical hem is a neuroepithelial tissue adjacent to the dorsal midline in the medial cortical wall, defined by its expression of multiple Bmps and Wnts [17, 27] (Figure 1). The distribution and timing of Bmp/Wnt expression in the cortical hem and their receptors in the cortex suggest that the cortical hem is involved in cortical patterning (e.g. [28]). However, by a comparison to the CoP, the function of the cortical hem in neocortical arealization has not been clearly defined. Genetic
Transcription factors that specify area identities of cortical progenitors
The telencephalic patterning centers described above in principle have the capacity to interact; for example, morphogens secreted by one patterning center can repress the expression of those expressed by another center (for review see [3, 4]). In addition, morphogens secreted by the CoP and cortical hem have prominent roles in establishing the graded expression of TFs in progenitors in the cortical VZ. These TFs meet the basic criteria required for candidate genes that specify area identities
Screens for genes differentially expressed along cortical axes and candidate target genes of TFs and morphogens that control cortical arealization
Defining the target genes of TFs that control arealization and determine how they function to generate area specializations is one of many major challenges for the future. An initial step in this process is to do large-scale screens to define candidate target genes. Some screens have been designed to identify additional genes that are differentially expressed within the cortex and therefore might be involved in arealization. The first reported screen of this type was a differential display PCR
Primary cortical areas exhibit significant variation in size between normal individuals
The general spatial relationship between the primary areas is largely conserved across mammals, though some animals with unusual or large and atypical peripheral appendages/sense organs (e.g. the platypus’ bill or the echo-location system in bats) have modifications on this general geometrical scheme of area patterning to reflect their sensory specializations [55]. A straightforward example of this concept comes from a comparison of area patterning in the mouse, ghost bat, and short-tailed
Behavioral implications of variation in area size
Recent studies in mice indicate that variations in area size within the ranges found between inbred mouse strains, and well below the ranges reported for normal humans, can have dramatic, modality-specific effects on behavior [36•]. For example, the alterations of the levels of Emx2 in cortical progenitors that result in either relatively modest decreases or increases in the sizes of somatosensory and motor areas in adult mice result in significant, and specific, deficiencies at tests of
Conclusion
The coming years look very promising for significant advances in understanding the mechanisms that control area patterning. The study of cortical arealization has captured the attention of a rapidly increasing number of investigators bringing to bear on the issue a diverse range of backgrounds and talents. In addition, the tools required for these studies, ranging from genetically engineered mice to databases, are expanding rapidly. The availability of fully sequenced genomes for strains of
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
Work in the authors’ lab on this topic is supported by NIH grants R37 NS31558 and R01 NS 050646. We thank Chuck Stevens and members of the O’Leary lab, particularly Shen-ju Chou, Todd Kroll, Axel Leingartner, Scott May, Carlos Perez-Garcia, Andreas Zembrzycki, for their contributions and helpful discussions.
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2020, Current Opinion in Genetics and DevelopmentCitation Excerpt :Additionally, neocortical myelination is protracted in humans [9,35] and oligodendrocytes, which create the myelin sheath, are selectively enriched for species-specific changes in regulatory elements (see below). While developmental mechanisms governing regional patterning of the rodent cerebral cortex have been characterized [38–42], the mechanisms underlying the development of the reciprocal connectivity between PFC and the mediodorsal nucleus of the thalamus (MD) and the lateral expansion of granular PFC in primates have not been described. Recent interrogation of human and macaque RNA-seq data identified a transcriptomic signature of a dorsolateral expansion of retinoic acid (RA) signaling in the midfetal macaque and human frontal cortex compared to mice [Shibata et al., bioRxiv doi: 10.1101/2019.12.31.891036].