ZIC1 and ZIC4 control cerebellar size and foliation by Shh dependent and indepenedent mechanisms

ZIC1 and ZIC4 are two causative genes in Dandy Walker malformation, the most common congenital cerebellar malformation in humans. This thesis describes detailed analysis of the mechanisms of Zic1 and Zic4 activity in Zic1 and Zic4 single and double homozygous mutant mice. The data presented here show that cerebellar granule cell proliferation is reduced in Zic1 and Zic4 mutant mice and this accounts for reduced cerebellar size in adult mutant cerebella. Shh target gene analysis shows that the Shh pathway is disrupted in Zic1 and Zic4 mutant cerebella and Zic1and Zic4 interact genetically with Shh to control cerebellar growth. Zic1 and Zic4 also work through Shh independent mechanisms to control cerebellar foliation and prepatterning of the cerebellar anlage. Microarray analysis was used to identify targets of Zic1 and Zic4 activity, and these data will be used to identify genes involved in Zic1 and Zic4 mediated cerebellar prepatterning and foliation.