Hippocampal development and neural stem cell maintenance require Sox2-dependent regulation of Shh
Hippocampal development and neural stem cell maintenance require Sox2-dependent regulation of Shh
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DOI：
10.1038/nn.2397
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发表时间：
2009-10-01
影响因子：
25
通讯作者：
Nicolis, Silvia K.
中科院分区：
文献类型：
--
作者：
Favaro, Rebecca;Valotta, Menella;Nicolis, Silvia K.
神经干细胞（Neural stem cells，NSCs）是受扩散因子控制的。转录因子Sox 2由NSC表达，并且人中的Sox 2突变导致脑中，特别是海马中的缺陷。我们在小鼠胚胎脑中删除了Sox 2。在出生时，小鼠表现出轻微的脑缺陷;然而，不久之后，海马体中的神经干细胞和神经发生完全消失，导致齿状回发育不全。成年小鼠Sox 2基因缺失也导致海马神经发生缺失。海马发育缺陷类似于晚期音刺猬（Shh）丢失引起的发育缺陷。在突变小鼠中，Shh和Wnt 3a在海马原基中不存在。SHH药理学激动剂部分挽救了海马缺陷。染色质免疫沉淀鉴定Shh为Sox 2靶。Sox 2缺失的神经干细胞在体外不表达Shh，并迅速丢失。它们的复制部分地通过添加SHH而被拯救，并且几乎完全通过来自正常细胞的条件培养基而被拯救。因此，神经干细胞至少部分地通过Sox 2依赖性自分泌机制控制其状态。
Neural stem cells (NSCs) are controlled by diffusible factors. The transcription factor Sox2 is expressed by NSCs and Sox2 mutations in humans cause defects in the brain and, in particular, in the hippocampus. We deleted Sox2 in the mouse embryonic brain. At birth, the mice showed minor brain defects; shortly afterwards, however, NSCs and neurogenesis were completely lost in the hippocampus, leading to dentate gyrus hypoplasia. Deletion of Sox2 in adult mice also caused hippocampal neurogenesis loss. The hippocampal developmental defect resembles that caused by late sonic hedgehog (Shh) loss. In mutant mice, Shh and Wnt3a were absent from the hippocampal primordium. A SHH pharmacological agonist partially rescued the hippocampal defect. Chromatin immunoprecipitation identified Shh as a Sox2 target. Sox2-deleted NSCs did not express Shh in vitro and were rapidly lost. Their replication was partially rescued by the addition of SHH and was almost fully rescued by conditioned medium from normal cells. Thus, NSCs control their status, at least partly, through Sox2-dependent autocrine mechanisms.