Trends in Genetics
ReviewGenetic mechanisms underlying abnormal neuronal migration in classical lissencephaly
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
References (64)
The dystroglycanopathies: the new disorders of O-linked glycosylation
Semin. Pediatr. Neurol.
(2005)doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein
Cell
(1998)Mutations in alpha-tubulin cause abnormal neuronal migration in mice and lissencephaly in humans
Cell
(2007)Targeted disruption of intracellular type I platelet activating factor-acetylhydrolase catalytic subunits causes severe impairment in spermatogenesis
J. Biol. Chem.
(2003)Magnetic resonance imaging and positron emission tomography of band heterotopia
Brain Dev.
(1993)Patient mutations in doublecortin define a repeated tubulin-binding domain
J. Biol. Chem.
(2000)Doublecortin kinase-2, a novel doublecortin-related protein kinase associated with terminal segments of axons and dendrites
J. Biol. Chem.
(2005)Spinophilin facilitates dephosphorylation of doublecortin by PP1 to mediate microtubule bundling at the axonal “wrist”
Cell
(2007)Doublecortin microtubule affinity is regulated by a balance of kinase and phosphatase activity at the leading edge of migrating neurons
Neuron
(2004)Cdk5 phosphorylation of doublecortin ser297 regulates its effect on neuronal migration
Neuron
(2004)
Neurabin II mediates doublecortin-dephosphorylation on actin filaments
Biochem. Biophys. Res. Commun.
Site-specific dephosphorylation of doublecortin (DCX) by protein phosphatase 1 (PP1)
Mol. Cell. Neurosci.
Genetic interactions between doublecortin and doublecortin-like kinase in neuronal migration and axon outgrowth
Neuron
Doublecortin-like kinase functions with doublecortin to mediate fiber tract decussation and neuronal migration
Neuron
zyg-8, a gene required for spindle positioning in C. elegans, encodes a doublecortin-like kinase
Dev. Cell
Doublecortin-like kinase controls neurogenesis by regulating mitotic spindles and M phase progression
Neuron
Ndel1 operates in a common pathway with LIS1 and cytoplasmic dynein to regulate cortical neuronal positioning
Neuron
The role of ARX in cortical development
Eur. J. Neurosci.
Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations
Nat. Genet.
The role of RELN in lissencephaly and neuropsychiatric disease
Am. J. Med. Genet. B. Neuropsychiatr. Genet.
Malformations of cortical development and epilepsy, part 1: diagnosis and classification scheme
Rev. Neurol. Dis.
Genotypically defined lissencephalies show distinct pathologies
J. Neuropathol. Exp. Neurol.
Lissencephaly and the molecular basis of neuronal migration
Hum. Mol. Genet.
A novel CNS gene required for neuronal migration and involved in X- linked subcortical laminar heterotopia and lissencephaly syndrome
Cell
Isolation of a Miller-Dieker lissencephaly gene containing G protein beta-subunit-like repeats
Nature
Loss of the Max-interacting protein Mnt in mice results in decreased viability, defective embryonic growth and craniofacial defects: relevance to Miller-Dieker syndrome
Hum. Mol. Genet.
Dictyostelium LIS1 is a centrosomal protein required for microtubule/cell cortex interactions, nucleus/centrosome linkage, and actin dynamics
Mol. Biol. Cell
Regulation of cytoplasmic dynein behaviour and microtubule organization by mammalian Lis1
Nat. Cell Biol.
NudF, a nuclear migration gene in Aspergillus nidulans, is similar to the human LIS-1 gene required for neuronal migration
Mol. Biol. Cell
Previously uncharacterized roles of platelet-activating factor acetylhydrolase 1b complex in mouse spermatogenesis
Proc. Natl. Acad. Sci. U. S. A.
The Pafah1b complex interacts with the Reelin receptor VLDLR
PLoS ONE
Subcortical laminar heterotopia and lissencephaly in two families: a single X linked dominant gene
J. Neurol. Neurosurg. Psychiatry
Cited by (106)
The One-Stop Gyrification Station - Challenges and New Technologies
2021, Progress in NeurobiologyModeling neurological disorders using brain organoids
2021, Seminars in Cell and Developmental BiologyCitation Excerpt :In contrast, mice, even with homozygous knockout of Dchs1 and Fat4, do not demonstrate abnormal cortical development [34]. This is similar in lissencephaly, a disease also with neuronal migration defects, where genetic mutations found in patients can yield modest or no relevant phenotypes in mouse models [35]. Thus, brain organoid models offer the opportunity for investigating underlying mechanisms of neuronal migration, especially those that may not be adequately recapitulated in other model systems.
Molecular mechanisms of cell polarity in a range of model systems and in migrating neurons
2020, Molecular and Cellular NeuroscienceLissencephalies and axon guidance disorders
2020, Neurodevelopmental Disorders: Comprehensive Developmental NeuroscienceMigration in the hippocampus
2020, Cellular Migration and Formation of Axons and Dendrites: Comprehensive Developmental Neuroscience