Trends in Genetics
Volume 23, Issue 12, December 2007, Pages 623-630
Journal home page for Trends in Genetics

Review
Genetic mechanisms underlying abnormal neuronal migration in classical lissencephaly

https://doi.org/10.1016/j.tig.2007.09.003Get rights and content

Classical lissencephaly is a human developmental brain disorder characterized by a paucity of cortical gyration and thickening of the cortical gray matter, leading to severe epilepsy and mental retardation. Loss-of-function mutations in the microtubule-associated protein encoding genes, PAFAH1B1 (encoding the protein LIS1), DCX and TUBA1A have been implicated in the pathogenesis of the condition. Animal models are required to understand the basis of this disease, which is a challenge, given that mice normally have a smooth cortex. Recent advances toward this goal have come from stepwise reduction in gene function, deletion of redundant genes and acute gene inactivation using short hairpin RNA (shRNA). These approaches have implicated genes that regulate the microtubule cytoskeleton during neuronal division, migration and maturation.

Section snippets

Development of the mammalian cerebral cortex

The formation of the complex architecture of the mammalian cerebral cortex (see Glossary) requires orchestrated movement of cells arising from different regions within the brain, and born at different times, to achieve specific laminar position, orientation and connections with other cells (see Figure I in Box 1). The striking morphology of neurons as they migrate, extend dendrites and axons and connect with other cells implies a strictly regulated program of cytoskeletal reorganization. Cell

Classical lissencephaly in humans

Human classical lissencephaly represents one of the most severe disorders of neocortical neuronal migration. It is characterized by a paucity of cortical gyration accompanied by thickening of the cortex. It is distinguished from the three other forms of lissencephaly based on the absence of additional characteristic features. For example, is it distinguished from (i) ‘cobblestone’ lissencephaly (i.e. lumpy-bumpy appearance of the cerebral cortex, which is caused by mutations of

Genetic basis of classical lissencephaly

Three distinct genetic causes for classical lissencephaly have been identified to date. Heterozygous mutations in platelet-activating factor acetylhydrolase 1B α subunit (PAFAH1B1, encoding the LIS1 protein), hemizygous mutations in the largely male-specific hemizygous doublecortin (DCX) or heterozygous mutations in tubulin α 1A (TUBA1A) are sufficient to produce varying severity of classical lissencephaly 8, 9, 10, 11. Although protein loss of function seems to underlie the disease in each

Mouse models of classical lissencephaly and disordered neuronal migration

Creation of animal models of human disease is key to understanding pathogenesis and testing possible therapies. One of the challenges in creating genetic mouse models of classical lissencephaly is that rodents do not display a gyrated cortex, and thus, it is not possible to model this feature of the brain malformation (Figure 1). Mice with heterozygous Pafah1b1 mutations (+/−) display only mildly disordered neuronal migration, with variation in correct positioning of cortical neurons evident at

Other potential roles for lissencephaly genes in brain development

Although there are clear defects in neuronal migration associated with disruption of Dcx or Lis1, there is also mounting evidence that these genes play important roles in other aspects of neuronal development, including cell division (i.e. mitosis of neural precursor cells) and maturation (elaboration of axons, dendrites and synaptic connections).

There is ample evidence that Lis1 has a mitotic function. Overexpression of Lis1 or injection of anti-Lis1 antibodies perturbs mitotic progress and

What have we learned about evolutionarily conserved requirements for lissencephaly genes?

There are obvious challenges in modeling classical lissencephaly in mice, given that, by their very nature, mice lack cortical gyri and sulci that characterize the human brain. Nevertheless, some basic principles have emerged from these studies.

  • (i)

    The highly complex human brain seems to be more susceptible to lissencephaly gene dosage reduction than the mouse brain in the genes that have been examined to date. This is not surprising given the relative increased complexity of the human cerebral

Future perspectives

Classical lissencephaly is a medically devastating, but scientifically fascinating, disease, because it can help inform us about the mechanisms of cerebral cortex development, as well as the underlying mechanisms of clinical mental retardation and epilepsy. The disease-causing genes identified to date account for a great majority of the disease; mutations are currently identified in >90% of cases. New insights could come from the identification of modifier genes that are naturally present in

Conflict of interest

The authors declare that they have no conflict of interest, real or apparent, with the publication or content of this manuscript.

Acknowledgements

The authors acknowledge the collaborative nature of the neuronal migration field, which has led to the sharing of preliminary data, resources and ideas, and has provided for rapid advancements in the field. The authors thank Anthony Wynshaw-Boris and anonymous reviewers for suggestions to improve this manuscript.

Glossary

Cerebral cortex
Refers to the gray and white matter that together form the convoluted outer structure of the central nervous system.
Corpus callosum
The main fiber bundle connecting the two hemispheres of the cerebral cortex.
CP
Cortical plate, region of the developing cortex populated by post migratory neurons. The cortical plate is organized in an inside out lamination with the latest born neurons located above the earliest ones, and will become the layers II to VI of the mature cortex.
Double

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