Multiple developmental programs are altered by loss of Zic1 and Zic4 to cause Dandy-Walker malformation cerebellar pathogenesis
Multiple developmental programs are altered by loss of Zic1 and Zic4 to cause Dandy-Walker malformation cerebellar pathogenesis
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DOI：
10.1242/dev.054114
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发表时间：
2011-03-15
期刊：
影响因子：
4.6
通讯作者：
Millen, Kathleen J.
中科院分区：
文献类型：
--
作者：
Blank, Marissa C.;Grinberg, Inessa;Millen, Kathleen J.
杂合缺失包括ZIC 1; ZIC 4基因座已被确定在一个子集的个人与常见的小脑出生缺陷Dandy-Walker畸形（DWM）。Zic 1和Zic 4在小鼠中的缺失产生类似于人类DWM的小脑大小和叶状缺陷，证实了这些基因在小脑发育中的需要，并提供了一个模型来描绘这种临床上重要的先天性畸形的发育基础。在这里，我们表明，减少小脑大小Zic 1和Zic 4突变体的结果，出生后颗粒祖细胞增殖减少。通过遗传和分子分析，我们发现Zic 1和Zic 4具有Shh依赖的促进颗粒祖细胞增殖的功能。Shh下游基因Ptch 1，Gli 1和Mycn的表达下调Zic 1/4突变体，虽然Shh生产和浦肯野细胞基因的表达是正常的。在Zic 1（+/-）; Zic 4（+/-）背景下减少Shh剂量也导致小脑尺寸减小和基因表达变化，与在Zic 1（-/-）; Zic 4（-/-）小鼠中观察到的结果相当。Zic 1和Zic 4还需要形成前蚓部叶状。Zic突变体叶图案异常与破坏小脑原基基因表达和浦肯野细胞地形在胚胎晚期阶段，然而，这种表型是嘘独立的。在Zic 1（+/-）; Zic 4（+/-）;Shh（+/-）中，我们观察到正常的小脑原基图案和叶状。此外，小脑模式在Gli 2-cko和Smo-cko突变小鼠中都是正常的，其中所有Shh功能都从发育中的小脑中移除。因此，我们的数据表明，Zic 1和Zic 4在小脑发育过程中既有Shh依赖的作用，也有独立的作用，并且多个发育中断是Zic 1/4相关DWM的基础。
Heterozygous deletions encompassing the ZIC1;ZIC4 locus have been identified in a subset of individuals with the common cerebellar birth defect Dandy-Walker malformation (DWM). Deletion of Zic1 and Zic4 in mice produces both cerebellar size and foliation defects similar to human DWM, confirming a requirement for these genes in cerebellar development and providing a model to delineate the developmental basis of this clinically important congenital malformation. Here, we show that reduced cerebellar size in Zic1 and Zic4 mutants results from decreased postnatal granule cell progenitor proliferation. Through genetic and molecular analyses, we show that Zic1 and Zic4 have Shh-dependent function promoting proliferation of granule cell progenitors. Expression of the Shh-downstream genes Ptch1, Gli1 and Mycn was downregulated in Zic1/4 mutants, although Shh production and Purkinje cell gene expression were normal. Reduction of Shh dose on the Zic1(+/-);Zic4(+/-) background also resulted in cerebellar size reductions and gene expression changes comparable with those observed in Zic1(-/-);Zic4(-/-) mice. Zic1 and Zic4 are additionally required to pattern anterior vermis foliation. Zic mutant folial patterning abnormalities correlated with disrupted cerebellar anlage gene expression and Purkinje cell topography during late embryonic stages; however, this phenotype was Shh independent. In Zic1(+/-);Zic4(+/-);Shh(+/-), we observed normal cerebellar anlage patterning and foliation. Furthermore, cerebellar patterning was normal in both Gli2-cko and Smo-cko mutant mice, where all Shh function was removed from the developing cerebellum. Thus, our data demonstrate that Zic1 and Zic4 have both Shh-dependent and -independent roles during cerebellar development and that multiple developmental disruptions underlie Zic1/4-related DWM.