Primary cilia regulate hippocampal neurogenesis by mediating sonic hedgehog signaling
Primary cilia regulate hippocampal neurogenesis by mediating sonic hedgehog signaling
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DOI：
10.1073/pnas.0804558105
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发表时间：
2008-09-02
影响因子：
11.1
通讯作者：
Town, Terrence
中科院分区：
文献类型：
--
作者：
Breunig, Joshua J.;Sarkisian, Matthew R.;Town, Terrence
初级纤毛存在于哺乳动物的神经元和神经胶质细胞上，但其功能在很大程度上是未知的。我们针对一个我们称为“短粗”（Stumpy）的基因培育了条件性纯合突变小鼠。突变体缺乏纤毛，并且在出生后发育的脑区有明显异常，包括一个发育不全的海马体，其特征是被称为星形胶质细胞样神经前体细胞（ALNPs）的神经干细胞的原发性缺乏。先前的研究表明初级纤毛介导音猬因子（Shh）信号传导。在此，我们发现ALNP纤毛的缺失导致Shh活性丧失、细胞周期退出增加以及ALNPs的形态异常。在缺乏纤毛的情况下，Shh信号传导的介质Gli3的加工过程也发生了改变。此外，Shh通路的关键介质定位于ALNP纤毛。因此，Shh机制对初级纤毛的选择性靶向赋予ALNPs与邻近细胞相比对Shh有丝分裂信号做出不同反应的能力。我们的数据表明这些细胞器是调节ALNP行为所必需的细胞“天线”。
Primary cilia are present on mammalian neurons and glia, but their function is largely unknown. We generated conditional homozygous mutant mice for a gene we termed Stumpy. Mutants lack cilia and have conspicuous abnormalities in postnatally developing brain regions, including a hypoplasic hippocampus characterized by a primary deficiency in neural stem cells known as astrocyte-like neural precursors (ALNPs). Previous studies suggested that primary cilia mediate sonic hedgehog (Shh) signaling. Here, we find that loss of ALNP cilia leads to abrogated Shh activity, increased cell cycle exit, and morphological abnormalities in ALNPs. Processing of Gli3, a mediator of Shh signaling, is also altered in the absence of cilia. Further, key mediators of the Shh pathway localize to ALNP cilia. Thus, selective targeting of Shh machinery to primary cilia confers to ALNPs the ability to differentially respond to Shh mitogenic signals compared to neighboring cells. Our data suggest these organelles are cellular "antennae" critically required to modulate ALNP behavior.