Disruption of SoxB1-dependent Sonic hedgehog expression in the hypothalamus causes septo-optic dysplasia.
Disruption of SoxB1-dependent Sonic hedgehog expression in the hypothalamus causes septo-optic dysplasia.
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DOI：
10.1016/j.devcel.2011.12.023
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发表时间：
2012-03-13
影响因子：
11.8
通讯作者：
Epstein, Douglas J.
中科院分区：
文献类型：
--
作者：
Zhao, Li;Zevallos, Solsire E.;Rizzoti, Karine;Jeong, Yongsu;Lovell-Badge, Robin;Epstein, Douglas J.
隔-视神经发育不良(SOD)是一种先天性脑畸形，导致垂体性、视神经和前脑中线缺陷。人们对超氧化物歧化酶的病因知之甚少，大多数病例是散发性的。在极少数情况下，超氧化物歧化酶是由Sox2、SOX3或Hesx1的突变引起的，但这在疾病中的表现还不完全确定。在这里，我们证明了在预期的下丘脑中缺乏Sonic Hedgehog(Shh)的小鼠胚胎表现出超氧化物歧化酶的关键特征，包括垂体发育不良和视盘缺失。Shh的下丘脑来源需要维持前后和内侧神经轴上的基因表达边界，这两个轴分别对正常的垂体和眼睛发育至关重要。我们进一步揭示了SOX2和SOX3是Shh转录的剂量依赖性调节因子，直接结合和激活一个长程Shh前脑增强子。这些数据表明，下丘脑Shh表达水平的降低会导致SOD。
Septo-optic dysplasia (SOD) is a congenital brain anomaly that results in pituitary, optic nerve, and midline forebrain defects. The etiology of SOD is poorly understood, with the majority of cases being sporadic. In rare instances, SOD is caused by mutations in Sox2, Sox3 or Hesx1, but how this manifests in disease is not entirely certain. We demonstrate here that mouse embryos lacking Sonic hedgehog (Shh) in the prospective hypothalamus exhibit key features of SOD, including pituitary hypoplasia and absence of the optic disc. The hypothalamic source of Shh is required to maintain gene expression boundaries along the anteroposterior and mediolateral neural axes that are important for proper pituitary and eye development, respectively. We further reveal that Sox2 and Sox3 are dose dependent regulators of Shh transcription, which directly bind and activate a long-range Shh forebrain enhancer. These data indicate that reduced levels of Shh expression in the hypothalamus cause SOD.
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