Lis1 is necessary for normal non-radial migration of inhibitory interneurons.
Type I lissencephaly is a central nervous system (CNS) malformation characterized by mental retardation and epilepsy. These clinical features suggest a deficit in inhibitory neurons may, in part, underlie the pathogenesis of this disorder. Mutations in, or deletions of, LIS1 are the most commonly recognized genetic anomaly associated with type I lissencephaly. The pathogenesis of type I lissencephaly is believed to be a defect in radial neuronal migration, a process requiring LIS1. In contrast the inhibitory neurons migrate non-radially from the basal forebrain to the neocortex and hippocampus. Given that Lis1 is expressed in all neurons, we hypothesized that Lis1 also functions in non-radial migrating inhibitory neurons. To test this hypothesis we used a combination of in vivo and in vitro studies with Lis1 mutant mice and found non-radial cell migration is also affected. Our data indicate Lis1 is required for normal non-radial neural migration and that the Lis1 requirement is primarily cell autonomous, although a small cell non-autonomous effect could not be excluded. These data indicate inhibitory neuron migration is slowed but not absent, similar to that found for radial cell migration. We propose that the defect in non-radial cell migration is likely to contribute to the clinical phenotype observed in individuals with a LIS1 mutation.
Neuroscience Program, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Matthew F
MF
McManus
Ilya M
IM
Nasrallah
MacLean M
MM
Pancoast
Anthony
A
Wynshaw-Boris
Jeffrey A
JA
Golden
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000818:Animals; D002465:Cell Movement; D004622:Embryo, Mammalian / Q000502:physiology*; D005260:Female; D006579:Heterozygote; D007395:Interneurons / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000502:physiology*; D009433:Neural Inhibition; D011247:Pregnancy; D011270:Pregnancy, Animal
D008869:Microtubule-Associated Proteins; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C513190:Pafah1b1 protein, mouse