Haldipur Parthiv, Dang Derek, Aldinger Kimberly A, Janson Olivia K, Guimiot Fabien, Adle-Biasette Homa, Dobyns William B, Siebert Joseph R, Russo Rosa, Millen Kathleen J
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States.
Hôpital Robert-Debré, INSERM UMR 1141, Paris, France.
Elife. 2017 Jan 16;6:e20898. doi: 10.7554/eLife.20898.
loss contributes to Dandy-Walker malformation (DWM), a common human cerebellar malformation. Previously, we found that complete loss leads to aberrations in proliferation, neuronal differentiation and migration in the embryonic mouse cerebellum (Haldipur et al., 2014). We now demonstrate that hypomorphic mutant mice have granule and Purkinje cell abnormalities causing subsequent disruptions in postnatal cerebellar foliation and lamination. Particularly striking is the presence of a partially formed posterior lobule which echoes the posterior vermis DW 'tail sign' observed in human imaging studies. Lineage tracing experiments in mutant mouse cerebella indicate that aberrant migration of granule cell progenitors destined to form the posterior-most lobule causes this unique phenotype. Analyses of rare human del chr 6p25 fetal cerebella demonstrate extensive phenotypic overlap with our mutant mouse models, validating our DWM models and demonstrating that many key mechanisms controlling cerebellar development are likely conserved between mouse and human.
缺失会导致丹迪-沃克畸形（DWM），这是一种常见的人类小脑畸形。此前，我们发现完全缺失会导致胚胎小鼠小脑中增殖、神经元分化和迁移出现异常（哈尔迪普尔等人，2014年）。我们现在证明，低表达突变小鼠存在颗粒细胞和浦肯野细胞异常，导致出生后小脑叶形成和分层随后受到破坏。特别引人注目的是存在一个部分形成的后叶，这与人类影像学研究中观察到的后蚓部DW“尾征”相似。对突变小鼠小脑进行的谱系追踪实验表明，注定要形成最尾端叶的颗粒细胞祖细胞异常迁移导致了这种独特的表型。对罕见的人类6号染色体短臂25区缺失胎儿小脑的分析表明，其与我们的突变小鼠模型存在广泛的表型重叠，验证了我们的DWM模型，并表明许多控制小脑发育的关键机制在小鼠和人类之间可能是保守的。
