Mash1 is required for generic and subtype differentiation of hypothalamic neuroendocrine cells
Mash1 is required for generic and subtype differentiation of hypothalamic neuroendocrine cells
复制标题
DOI：
10.1210/me.2005-0518
复制
发表时间：
2006-07-01
影响因子：
--
通讯作者：
Ang, Siew-Lan
中科院分区：
文献类型：
--
作者：
McNay, David E. G.;Pelling, Michelle;Ang, Siew-Lan
神经内分泌下丘脑调节许多关键的生物过程，是从生长障碍到肥胖等一系列疾病的基础。尽管对下丘脑功能的阐明已取得很大进展，但对下丘脑发育的了解还很匮乏。特别是，人们对腹侧核、弓状核和腹内侧核神经元的神经发生和规格的潜在过程知之甚少。原神经基因 Mash1 在整个基底视交叉后神经上皮中表达，Mash1 的缺失会导致弓状核和腹内侧核发育不全。这些缺陷是由于神经发生和细胞凋亡的失败造成的，这种缺陷可以通过 Mash1 启动子控制下的异位 Ngn2 来挽救。除了在神经发生中的作用外，对 Mash1(-/-)、Mash1(+/-)、Mash1(KINgn2/KINgn2) 和 Mash1(KINgn2/+) 小鼠的分析表明，Mash1 是 Gsh1 表达和随后的 GHRH 表达所特别需要的，正向调节 SF1 表达，并抑制酪氨酸羟化酶 (TH) 和神经肽 Y (NPY) 表达。虽然 Mash1 不是丙黑皮素 (POMC) 表达所必需的，但它是 POMC+ 神经元正常发育所必需的。这些数据表明，Mash1 不仅是腹侧神经内分泌神经元生成所必需的，而且在这些神经元的亚型规范中发挥着核心作用。
The neuroendocrine hypothalamus regulates a number of critical biological processes and underlies a range of diseases from growth failure to obesity. Although the elucidation of hypothalamic function has progressed well, knowledge of hypothalamic development is poor. In particular, little is known about the processes underlying the neurogenesis and specification of neurons of the ventral nuclei, the arcuate and ventromedial nuclei. The proneural gene Mash1 is expressed throughout the basal retrochiasmatic neuroepithelium and loss of Mash1 results in hypoplasia of both the arcuate and ventromedial nuclei. These defects are due to a failure of neurogenesis and apoptosis, a defect that can be rescued by ectopic Ngn2 under the control of the Mash1 promoter. In addition to its role in neurogenesis, analysis of Mash1(-/-), Mash1(+/-), Mash1(KINgn2/KINgn2), and Mash1(KINgn2/+) mice demonstrates that Mash1 is specifically required for Gsh1 expression and subsequent GHRH expression, positively regulates SF1 expression, and suppresses both tyrosine hydroxylase (TH) and neuropeptide Y (NPY) expression. Although Mash1 is not required for propiomelanocortin ( POMC) expression, it is required for normal development of POMC+ neurons. These data demonstrate that Mash1 is both required for the generation of ventral neuroendocrine neurons as well as playing a central role in subtype specification of these neurons.