Zic2Controls Cerebellar Development in Cooperation withZic1

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Abstract
Mouse Zic genes encode zinc finger proteins and are expressed in the developing and mature CNS. Reduced expression of Zic2 in mice results in spina bifida and holoprosencephaly. However, the disruption of Zic1, a strong homolog of Zic2 that has an overlapping expression pattern, results in cerebellar malformation with no apparent abnormalities in the forebrain or in posterior neuropore closure. Here we revealed that Zic2 and Zic1cooperatively control cerebellar development by regulating neuronal differentiation. Both Zic1 and Zic2 are expressed in the precursor cells of the granule neuron and the neurons in cerebellar nuclei. Mice carrying one mutatedZic1 allele together with one mutatedZic2 allele (Zic1+/−Zic2+/kd) showed a marked cerebellar folial abnormality similar to, but distinct from that found in mice homozygous for the Zic1 mutation (Zic1−/−). TheZic1+/−Zic2+/kdcerebellum is missing a lobule in the anterior vermis and has a truncation of the most posterior lobule. Expression of transverse zonal markers is shifted anteriorly in the developing cerebellum, indicating that the anterior part of the cerebellum is poorly developed. Abnormalities in the developingZic1+/−Zic2+/kdcerebellum share the following features with those of theZic1−/− cerebellum: a preceding reduction of cell proliferation in the anterior external germinal layer, a reduction in cyclin D1 expression, and enhanced expression of the mitosis inhibitors p27 andp16, and enhancement of Wnt7a expression. These results indicate that Zic1 and Zic2 may have very similar functions in the regulation of cerebellar development.