Multiple developmental programs are altered by loss ofZic1andZic4to cause Dandy-Walker malformation cerebellar pathogenesis
| Autor: | Christine L. Laliberté, Inessa Grinberg, R. Mark Henkelman, Marissa C. Blank, Kathleen J. Millen, Emmanuel Aryee, Victor V. Chizhikov |
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| Rok vydání: | 2011 |
| Předmět: |
Cerebellum
Mutant Purkinje cell Biology ZIC1 Mice Dandy–Walker syndrome Pregnancy medicine Animals Humans Hedgehog Proteins Progenitor cell Molecular Biology Research Articles Cell Proliferation Homeodomain Proteins Mice Knockout Genetics Regulation of gene expression Gene Expression Regulation Developmental Organ Size Embryo Mammalian medicine.disease Granule cell Cell biology medicine.anatomical_structure Animals Newborn Female Dandy-Walker Syndrome Transcription Factors Developmental Biology |
| Zdroj: | Development. 138:1207-1216 |
| ISSN: | 1477-9129 0950-1991 |
| DOI: | 10.1242/dev.054114 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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