LIS1: cellular function of a disease-causing gene

doi:10.1016/S0962-8924(01)01956-0

Trends in Cell Biology

Volume 11, Issue 4, 1 April 2001, Pages 155-160

https://doi.org/10.1016/S0962-8924(01)01956-0 Get rights and content

Abstract

Brain development is severely defective in children with lissencephaly. The highly organized distribution of neurons within the cerebral cortex is disrupted, a condition that might arise from improper migration of neuronal progenitors to their cortical destinations. Type I lissencephaly results from mutations in the LIS1 gene, which has been implicated in the cytoplasmic dynein and platelet-activating factor pathways. Recent studies have identified roles for the product of LIS1 in nuclear migration, mitotic spindle orientation and chromosome alignment, where it appears to act in concert with cytoplasmic dynein. A unifying hypothesis for the subcellular function of LIS1 is presented.

Section snippets

Range of LIS1 functions based on genetic studies

The first LIS1-related gene identified outside of vertebrates was nudF in the mold Aspergillus nidulans ⁴. nudF and human LIS1 are homologous throughout the length of their coding regions, suggesting that they might be orthologs. Mutations in nudF caused a severe defect in the migration of nuclei into and within the hyphal processes, resulting in grossly diminished colony size. This evidence seemed of immediate interest in understanding lissencephaly because it suggested a related function for

Cellular and molecular analysis

Recent cellular and molecular analysis of LIS1 in mammalian systems has helped to define the cellular role of LIS1 more precisely. Both cytoplasmic dynein and dynactin were found to coimmunoprecipitate with LIS1 from mammalian cell and tissue extracts 13, 14. This represents the first evidence that LIS1 physically interacts with components of the dynein, as well as the PAF acetylhydrolase, pathway. The interaction of both the dynein and dynactin complexes with LIS1 is noteworthy, suggesting

Unifying features of LIS1 function

Together, the existing data on the cellular function of LIS1 appear to make an indisputable case for a role in the cytoplasmic dynein pathway. How does this conclusion relate to evidence for a role in the PAF pathway? First, the phenotypic evidence from lower eukaryotes can be interpreted largely or exclusively in terms of a defect in cytoplasmic dynein regulation. Furthermore, coding sequence for the catalytic subunits of PAF acetylhydrolase is lacking in yeast and is sufficiently divergent in

Role of LIS1 in disease

Research into the developmental and cellular role of LIS1 and its homologs has suggested two potential causes for the disorganized architecture of the lissencephalic brain. First, LIS1 clearly participates in regulating nuclear movement in organisms ranging from yeast to mouse. The extent to which defects in nuclear migration interfere with translocation of the entire neuron is uncertain, and it will be of considerable interest to explore this issue further. LIS1 has now also been implicated in

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Trends in Cell Biology

OpinionLIS1: cellular function of a disease-causing gene

Abstract

Section snippets

Range of LIS1 functions based on genetic studies

Cellular and molecular analysis

Unifying features of LIS1 function

Role of LIS1 in disease

Dev. Biol.

Curr. Biol.

J. Biol. Chem.

Mech. Dev.

Curr. Biol.

Curr. Biol.

FEBS Lett.

Neuron

Neuron

Neuron

Isolation of a Miller–Dieker lissencephaly gene containing G protein β-subunit-like repeats

Nature

Point mutations and an intragenic deletion in LIS1, the lissencephaly causative gene in isolated lissencephaly sequence and Miller–Dieker syndrome

Hum. Mol. Genet.

Miller–Dieker lissencephaly gene encodes a subunit of brain platelet-activating factor

Nature

NudF, a nuclear migration gene in Aspergillus nidulans, is similar to the human LIS-1 gene required for neuronal migration

Mol. Biol. Cell

Mutations in the heavy chain of cytoplasmic dynein suppress the nudF nuclear migration mutation of Aspergillus nidulans

Mol. Gen. Genet.

Saccharomyces cerevisiae genes required in the absence of the CIN8-encoded spindle motor act in functionally diverse mitotic pathways

Mol. Biol. Cell

Drosophila lissencephaly-1 functions with Bic-D and dynein in oocyte determination and nuclear positioning

Nat. Cell Biol.

Lis1, the Drosophila homolog of a human lissencephaly disease gene, is required for germline cell division and oocyte differentiation

Development

Opinion
LIS1: cellular function of a disease-causing gene