Desert Hedgehog Links Transcription Factor Sox10 to Perineurial Development
Desert Hedgehog Links Transcription Factor Sox10 to Perineurial Development
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DOI：
10.1523/jneurosci.5759-11.2012
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发表时间：
2012-04-18
影响因子：
5.3
通讯作者：
Wegner, Michael
中科院分区：
文献类型：
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作者：
Kuespert, Melanie;Weider, Matthias;Wegner, Michael
雪旺细胞是PNS中主要的胶质细胞类型。它们在胚胎发生过程中沿着沿着神经发育，并依赖于含有Sox 10转录因子的HMG结构域进行特化、谱系进展和终末分化。Sox10在未成熟的雪旺细胞中的缺失导致小鼠的外周神经缺陷，这些缺陷并不限于这种胶质细胞类型，尽管在神经中的表达和基因丢失是。例如，作为保护鞘的神经束膜的形成严重受损。这类似于在小鼠中失去沙漠刺猬（Dhh）后观察到的缺陷。在这里，我们表明，Sox10激活Dhh的表达在许旺细胞通过增强子，位于Dhh基因的内含子1。Sox10通过几个位点以单体形式结合该增强子。这些位点的突变废除了体外和转基因小鼠胚胎中的Schwann细胞特异性活性和Sox10反应性。这表明Sox10通过直接结合增强子激活Dhh表达，并通过增加Dhh水平促进神经束膜鞘的形成。这代表了Sox 10在外周神经发育过程中的非细胞自主功能的第一种机制。
Schwann cells are the main glial cell type in the PNS. They develop along nerves during embryogenesis and rely on the HMG domain containing Sox10 transcription factor for specification, lineage progression, and terminal differentiation. Sox10 deletion in immature Schwann cells caused peripheral nerve defects in mice that were not restricted to this glial cell type, although expression in the nerve and gene loss were. Formation of the perineurium as the protecting sheath was, for instance, heavily compromised. This resembled the defect observed after loss of Desert hedgehog (Dhh) in mice. Here we show that Sox10 activates Dhh expression in Schwann cells via an enhancer that is located in intron 1 of the Dhh gene. Sox10 binds this enhancer in monomeric form via several sites. Mutation of these sites abolishes both Schwann-cell-specific activity and Sox10 responsiveness in vitro and in transgenic mouse embryos. This argues that Sox10 activates Dhh expression by direct binding to the enhancer and by increasing Dhh levels promotes formation of the perineurial sheath. This represents the first mechanism for a non-cell-autonomous function of Sox10 during peripheral nerve development.