Zic2 controls cerebellar development in cooperation with Zic1
Zic2 controls cerebellar development in cooperation with Zic1
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DOI：
10.1523/jneurosci.22-01-00218.2002
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发表时间：
2002-01-01
影响因子：
5.3
通讯作者：
Mikoshiba, K
中科院分区：
文献类型：
--
作者：
Aruga, J;Inoue, T;Mikoshiba, K
小鼠Zic基因编码锌指蛋白，并在发育和成熟的CNS中表达。Zic 2在小鼠中的表达减少导致脊柱裂和前脑无裂畸形。然而，Zic 1，Zic 2的一个强同源物，具有重叠的表达模式，在小脑畸形的前脑或后神经孔闭合没有明显的异常的结果中断。在这里，我们揭示了Zic 2和Zic 1通过调节神经元分化来协同控制小脑发育。Zic 1和Zic 2均表达于颗粒神经元的前体细胞和小脑核的神经元。携带一个突变的Zic 1等位基因和一个突变的Zic 2等位基因（Zic 1（+/-）Zic 2（+/kd））的小鼠显示出明显的小脑叶异常，与Zic 1突变纯合子（Zic 1（-/-））小鼠相似，但不同。Zic 1（+/-）Zic 2（+/kd）小脑在前蚓部缺少一个小叶，并且最后小叶被截断。在发育中的小脑中，横带标记物的表达向前移动，表明小脑的前部发育不良。发育中的Zic 1（+/-）Zic（2+/kd）小脑的凋亡与Zic 1（-/-）小脑的凋亡具有以下特征：前外胚层细胞增殖减少，细胞周期蛋白D1表达减少，有丝分裂抑制剂p27和p16表达增强，Wnt 7a表达增强。这些结果表明，Zic 1和Zic 2在小脑发育的调节中可能具有非常相似的功能。
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 Zic1 cooperatively 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 mutated Zic1 allele together with one mutated Zic2 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(-/-)). The Zic1(+/-)Zic2(+/kd) cerebellum 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 developing Zic1(+/-)Zic(2+/kd) cerebellum share the following features with those of the Zic1(-/-) 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 and p16, and enhancement of Wnt7a expression. These results indicate that Zic1 and Zic2 may have very similar functions in the regulation of cerebellar development.