Lis1 mutation prevents basal radial glia-like cell production in the mouse

Maxime Penisson (1) , Mingyue Jin (2) , Shengming Wang (2) , Shinji Hirotsune (2) , Fiona Francis (1) , Richard Belvindrah (1)

1 IFM - Inserm U1270 - SU - Institut du Fer à Moulin
2 Graduate School of Medicine [Osaka]

Abstract Human cerebral cortical malformations are associated with progenitor proliferation and neuronal migration abnormalities. Progenitor cells include apical radial glia, intermediate progenitors and basal (or outer) radial glia (bRGs or oRGs). bRGs are few in number in lissencephalic species (e.g. the mouse) but abundant in gyrencephalic brains. The LIS1 gene coding for a dynein regulator, is mutated in human lissencephaly, associated also in some cases with microcephaly. LIS1 was shown to be important during cell division and neuronal migration. Here, we generated bRG-like cells in the mouse embryonic brain, investigating the role of Lis1 in their formation. This was achieved by in utero electroporation of a hominoid-specific gene TBC1D3 (coding for a RAB-GAP protein) at mouse embryonic day (E) 14.5. We first confirmed that TBC1D3 expression in wild-type (WT) brain generates numerous Pax6+ bRG-like cells that are basally localized. Second, using the same approach, we assessed the formation of these cells in heterozygote Lis1 mutant brains. Our novel results show that Lis1 depletion in the forebrain from E9.5 prevented subsequent TBC1D3-induced bRG-like cell amplification. Indeed, we observe perturbation of the ventricular zone (VZ) in the mutant. Lis1 depletion altered adhesion proteins and mitotic spindle orientations at the ventricular surface and increased the proportion of abventricular mitoses. Progenitor outcome could not be further altered by TBC1D3. We conclude that disruption of Lis1/LIS1 dosage is likely to be detrimental for appropriate progenitor number and position, contributing to lissencephaly pathogenesis.

Domaines: Biochimie, Biologie Moléculaire

Maxime Penisson, Mingyue Jin, Shengming Wang, Shinji Hirotsune, Fiona Francis, et al.. Lis1 mutation prevents basal radial glia-like cell production in the mouse. Human Molecular Genetics, 2021, ⟨10.1093/hmg/ddab295⟩. ⟨hal-03379982⟩