Multiple developmental programs are altered by loss of Zic1 and Zic4 to cause Dandy-Walker malformation cerebellar pathogenesis

Development. 2011 Mar;138(6):1207-16. doi: 10.1242/dev.054114. Epub 2011 Feb 9.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Animals, Newborn
  • Cell Proliferation
  • Cerebellum / abnormalities*
  • Cerebellum / embryology*
  • Cerebellum / metabolism
  • Cerebellum / pathology
  • Dandy-Walker Syndrome / embryology*
  • Dandy-Walker Syndrome / genetics*
  • Dandy-Walker Syndrome / metabolism
  • Dandy-Walker Syndrome / pathology
  • Embryo, Mammalian
  • Female
  • Gene Expression Regulation, Developmental
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism
  • Hedgehog Proteins / physiology
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Homeodomain Proteins / physiology
  • Humans
  • Mice
  • Mice, Knockout
  • Organ Size / genetics
  • Pregnancy
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcription Factors / physiology

Substances

  • Hedgehog Proteins
  • Homeodomain Proteins
  • Shh protein, mouse
  • Transcription Factors
  • Zic1 protein, mouse
  • Zic4 protein, mouse