Phenotypic outcomes in Mouse and Human Foxc1 dependent Dandy-Walker cerebellar malformation suggest shared mechanisms.
Phenotypic outcomes in Mouse and Human Foxc1 dependent Dandy-Walker cerebellar malformation suggest shared mechanisms.
复制标题
小鼠和人类FOXC1依赖的dandy-walker小脑畸形中的表型结局提出了共同的机制。
DOI：
10.7554/elife.20898
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发表时间：
2017-01-16
期刊：
影响因子：
7.7
通讯作者：
Millen KJ
中科院分区：
文献类型：
--
作者：
Haldipur P;Dang D;Aldinger KA;Janson OK;Guimiot F;Adle-Biasette H;Dobyns WB;Siebert JR;Russo R;Millen KJ
FOXC1 缺失会导致 Dandy-Walker 畸形 (DWM)，这是一种常见的人类小脑畸形。此前，我们发现Foxc1完全缺失会导致胚胎小鼠小脑的增殖、神经元分化和迁移异常。我们现在证明，低等位的 Foxc1 突变小鼠具有颗粒和浦肯野细胞异常，导致出生后小脑叶状结构和层状结构的破坏。特别引人注目的是部分形成的后小叶的存在，与人体成像研究中观察到的后蚓部 DW“尾部标志”相呼应。 Foxc1 突变小鼠小脑的谱系追踪实验表明，注定要形成最后小叶的颗粒细胞祖细胞的异常迁移导致了这种独特的表型。对罕见人类 del chr 6p25 胎儿小脑的分析表明与我们的 Foxc1 突变小鼠模型存在广泛的表型重叠，验证了我们的 DWM 模型并证明控制小脑发育的许多关键机制可能在小鼠和人类之间是保守的。 DOI：http://dx.doi.org/10.7554/eLife.20898.001
FOXC1 loss contributes to Dandy-Walker malformation (DWM), a common human cerebellar malformation. Previously, we found that complete Foxc1 loss leads to aberrations in proliferation, neuronal differentiation and migration in the embryonic mouse cerebellum. We now demonstrate that hypomorphic Foxc1 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 Foxc1 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 Foxc1 mutant mouse models, validating our DWM models and demonstrating that many key mechanisms controlling cerebellar development are likely conserved between mouse and human. DOI: http://dx.doi.org/10.7554/eLife.20898.001