Primary cilia are required for cerebellar development and Shh-dependent expansion of progenitor pool
Primary cilia are required for cerebellar development and Shh-dependent expansion of progenitor pool
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DOI：
10.1016/j.ydbio.2008.02.026
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发表时间：
2008-05-01
影响因子：
2.7
通讯作者：
Alvarez-Buylla, A.
中科院分区：
文献类型：
--
作者：
Spassky, N.;Han, Y. -G.;Alvarez-Buylla, A.
小脑颗粒细胞前体细胞（GCPs）是哺乳动物大脑中最丰富的神经元类型，起源于菱形唇（RL）中有限的初级祖细胞库。由发育中的浦肯野细胞分泌的Sonic hedgehog（Shh）对于GCPs的扩增和小脑形态发生是必不可少的。最近的研究表明，初级纤毛集中Shh信号的成分，这种结构是Shh信号所必需的。GCP在其表面上具有初级纤毛[Del Cerro，M. P.，Snider，R.S.（1972年）。关于小脑发育的研究。二.外颗粒层的超微结构。J Comp Neurol 144，131-64.]。在这里，我们表明，1）这种纤毛可以有条件地消融Kif 3a（fl/-）小鼠与hGFAP-Cre小鼠杂交，2）Kif 3a从GCPs的去除破坏小脑发育，和3）这些缺陷是由于Shh依赖的GCPs扩增急剧减少。当Smoothened（Smo）（Shh信号传导的重要转导子）从相同的GCP群体中去除时，观察到类似的表型。有趣的是，Kif 3a-Smo双条件突变体显示Kif 3a对Smo具有上位性。这项工作表明Kif 3a对于小脑祖细胞的Shh依赖性扩增至关重要。纤毛功能障碍与多种人类疾病相关，包括Bardet-Biedl和Joubert综合征。在这些患者中观察到的小脑异常可以解释为Shh诱导的GCP扩展缺陷。(C)2008年爱思唯尔公司All rights reserved.
Cerebellar granule cell precursors (GCPs), which give rise to the most abundant neuronal type in the mammalian brain, arise from a restricted pool of primary progenitors in the rhombic lip (RL). Sonic hedgehog (Shh) secreted by developing Purkinje cells is essential for the expansion of GCPs and for cerebellar morphogenesis. Recent studies have shown that the primary cilium concentrates components of Shh signaling and that this structure is required for Shh signaling. GCPs have a primary cilium on their surface [Del Cerro, M.P., Snider, R.S. (1972). Studies on the developing cerebellum. II. The ultrastructure of the external granular layer. J Comp Neurol 144, 131-64.]. Here, we show that 1) this cilium can be conditionally ablated by crossing Kif3a(fl/-) mice with hGFAP-Cre mice, 2) removal of Kif3a from GCPs disrupts cerebellar development, and 3) these defects are due to a drastic reduction in Shh-dependent expansion of GCPs. A similar phenotype is observed when Smoothened (Smo), an essential transducer of Shh signaling, is removed from the same population of GCPs. Interestingly, Kif3a-Smo double conditional mutants show that Kif3a is epistatic to Smo. This work shows that Kif3a is essential for Shh-dependent expansion of cerebellar progenitors. Dysfunctional cilia are associated with diverse human disorders including Bardet-Biedl and Joubert syndromes. Cerebellar abnormalities observed in these patients could be explained by defects in Shh-induced GCP expansion. (C) 2008 Elsevier Inc. All rights reserved.