Development of neuroendocrine lineages requires the bHLH-PAS transcription factor SIM1
Development of neuroendocrine lineages requires the bHLH-PAS transcription factor SIM1
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DOI：
10.1101/gad.12.20.3264
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发表时间：
1998-10-15
影响因子：
10.5
通讯作者：
Fan, CM
中科院分区：
文献类型：
--
作者：
Michaud, JL;Rosenquist, T;Fan, CM
bHLH-PAS转录因子SIM 1在下丘脑-垂体轴发育期间在三个下丘脑核中表达：室旁核（PVN）、前室周核（aPV）和视上核（SON）。为了研究Sim 1在下丘脑中的功能，我们通过基因打靶产生了携带Sim 1无效等位基因的小鼠。纯合子突变小鼠出生后不久死亡。组织学分析表明，这些小鼠的PVN和SON细胞减少。突变体PVN、aPV和SON中不存在至少五种不同类型的分泌神经元，通过催产素、加压素、促甲状腺激素释放激素、促肾上腺皮质激素释放激素和生长激素抑制素的表达来识别。此外，我们表明，SIM 1控制这些分泌神经元的发展，在其分化的最后阶段。PVN/SON中这些神经元谱系的子集在携带POU转录因子BRN 2突变的小鼠中也缺失。我们提供的证据表明，在发展的Sim 1突变体下丘脑，未来PVN/SON地区未能表达Brn 2。我们的研究结果强烈表明，SIM 1的功能上游维持Brn 2的表达，这反过来又指导PVN/SON内的特定神经内分泌谱系的终末分化。
The bHLH-PAS transcription factor SIM1 is expressed during the development of the hypothalamic-pituitary axis in three hypothalamic nuclei: the paraventricular nucleus (PVN), the anterior periventricular nucleus (aPV), and the supraoptic nucleus (SON). To investigate Sim1 function in the hypothalamus, we produced mice carrying a null allele of Sim1 by gene targeting. Homozygous mutant mice die shortly after birth. Histological analysis shows that the PVN and the SON of these mice are hypocellular. At least five distinct types of secretory neurons, identified by the expression of oxytocin, vasopressin, thyrotropin-releasing hormone, corticotropin-releasing hormone, and somatostatin, are absent in the mutant PVN, aPV, and SON. Moreover, we show that SIM1 controls the development of these secretory neurons at the final stages of their differentiation. A subset of these neuronal lineages in the PVN/SON are also missing in mice bearing a mutation in the POU transcription factor BRN2. We provide evidence that, during development of the Sim1 mutant hypothalamus, the prospective PVN/SON region fails to express Brn2. Our results strongly indicate that SIM1 functions upstream to maintain Brn2 expression, which in turn directs the terminal differentiation of specific neuroendocrine lineages within the PVN/SON.