Notch/Rbpjκ signaling regulates progenitor maintenance and differentiation of hypothalamic arcuate neurons
Notch/Rbpjκ signaling regulates progenitor maintenance and differentiation of hypothalamic arcuate neurons
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DOI：
10.1242/dev.098681
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发表时间：
2013-09-01
期刊：
影响因子：
4.6
通讯作者：
Raetzman, Lori T.
中科院分区：
文献类型：
--
作者：
Aujla, Paven K.;Naratadam, George T.;Raetzman, Lori T.
下丘脑弓状核（Arc）内含有促黑素皮质素原（POMC）、神经肽Y（NPY）和生长激素释放激素（GHRH）神经元，对摄食、能量平衡和体尺大小起调节作用。这种自我平衡调节剂的失调是从生长障碍到肥胖症等疾病的基础。尽管对Arc神经元的功能进行了大量研究，但其发育机制仍不清楚。Notch信号传导因子如Hes 1和Mash 1存在于产生Arc神经元的下丘脑祖细胞中。然而，Notch信号传导如何控制这些祖细胞群体是未知的。为了阐明Notch信号传导在Arc发育中的作用，我们分析了在Nkx2.1-cre表达细胞中缺乏必要的Notch辅因子Rbpj kappa的条件性功能丧失小鼠（Rbpj kappa cKO），以及在Nkx2.1-cre表达细胞中表达组成型活性Notch 1胞内结构域（NICD）的小鼠（NICD Tg）。我们发现Rbpj κ的缺失导致E13.5时原始Arc内Hes 1的缺失，而Hes 5的缺失。此外，Mash 1表达增加，与E13.5时Arc神经元的增殖和积累增加一致。在E18.5，Rbpj kappa cKO小鼠的祖细胞很少，并且显示出分化的Pomc、NPY和Ghrh神经元数量增加。相比之下，NICD Tg小鼠具有增加的下丘脑祖细胞，在E18.5时显示不存在分化的Arc神经元和异常的胶质细胞分化。随后，Rbpj kappa cKO和NICD Tg小鼠在出生后发育期间的生长和体型都发生了变化。总之，我们的研究结果表明，Notch/Rbpj κ信号调节Arc神经元的产生和分化，这有助于身体大小的稳态调节。
The hypothalamic arcuate nucleus (Arc), containing pro-opoiomelanocortin (POMC), neuropeptide Y (NPY) and growth hormone releasing hormone (GHRH) neurons, regulates feeding, energy balance and body size. Dysregulation of this homeostatic mediator underlies diseases ranging from growth failure to obesity. Despite considerable investigation regarding the function of Arc neurons, mechanisms governing their development remain unclear. Notch signaling factors such as Hes1 and Mash1 are present in hypothalamic progenitors that give rise to Arc neurons. However, how Notch signaling controls these progenitor populations is unknown. To elucidate the role of Notch signaling in Arc development, we analyzed conditional loss-of-function mice lacking a necessary Notch co-factor, Rbpj kappa, in Nkx2.1-cre-expressing cells (Rbpj kappa cKO), as well as mice with expression of the constitutively active Notch1 intracellular domain (NICD) in Nkx2.1-cre-expressing cells (NICD Tg). We found that loss of Rbpj kappa results in absence of Hes1 but not of Hes5 within the primordial Arc at E13.5. Additionally, Mash1 expression is increased, coincident with increased proliferation and accumulation of Arc neurons at E13.5. At E18.5, Rbpj kappa cKO mice have few progenitors and show increased numbers of differentiated Pomc, NPY and Ghrh neurons. By contrast, NICD Tg mice have increased hypothalamic progenitors, show an absence of differentiated Arc neurons and aberrant glial differentiation at E18.5. Subsequently, both Rbpj kappa cKO and NICD Tg mice have changes in growth and body size during postnatal development. Taken together, our results demonstrate that Notch/Rbpj kappa signaling regulates the generation and differentiation of Arc neurons, which contribute to homeostatic regulation of body size.