Rax is a selector gene for mediobasal hypothalamic cell types.
Rax is a selector gene for mediobasal hypothalamic cell types.
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DOI：
10.1523/jneurosci.0913-12.2013
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发表时间：
2013-01-02
期刊：
影响因子：
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通讯作者：
Kurrasch DM
中科院分区：
文献类型：
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作者：
Lu F;Kar D;Gruenig N;Zhang ZW;Cousins N;Rodgers HM;Swindell EC;Jamrich M;Schuurmans C;Mathers PH;Kurrasch DM
大脑在控制能量、葡萄糖和脂质体内平衡中起着核心作用，下丘脑内侧基底核（即弓状核（ARC）和腹内侧核（VMH））内的专门神经元负责适当的信号整合。精确的细胞结构和潜在的电路如何在这些核团中建立仍然是未知的，部分原因是下丘脑发育程序刚刚开始被阐明。在这里，我们证明了视网膜和前神经折叠同源框（Rax）基因在建立小鼠ARC和VMH核中起着关键作用。首先，我们表明，Rax的ARC和VMH的祖细胞在整个发展中表达，因此，遗传命运定位研究表明，Rax+谱系引起VMH神经元。第二，使用Shh基因Cre驱动程序在VMH祖细胞亚群中有条件地消融Rax导致从VMH神经元表型到下丘脑但非VMH身份的命运转换，表明Rax是VMH细胞命运的选择基因。最后，使用Six 3 β Cre在整个ARC/VMH祖细胞中更广泛地消除Rax导致VMH和ARC细胞表型的严重损失，证明Rax在VMH和ARC命运特化中的作用。结合起来，我们的研究表明，Rax是需要在ARC/VMH祖细胞指定神经元表型在这个下丘脑脑区。因此，Rax提供了一个分子的切入点，为进一步研究的本体论和建立下丘脑进食回路。
The brain plays a central role in controlling energy, glucose, and lipid homeostasis, with specialized neurons within nuclei of the mediobasal hypothalamus, namely the arcuate (ARC) and ventromedial (VMH), tasked with proper signal integration. Exactly how the exquisite cytoarchitecture and underlying circuitry become established within these nuclei remains largely unknown, in part because hypothalamic developmental programs are just beginning to be elucidated. Here, we demonstrate that the Retinal and anterior neural fold homeobox (Rax) gene plays a key role in establishing ARC and VMH nuclei in mice. First, we show that Rax is expressed in ARC and VMH progenitors throughout development, and accordingly, genetic fate mapping studies reveal that Rax+ lineages give rise to VMH neurons. Second, the conditional ablation of Rax in a subset of VMH progenitors using a Shh∷Cre driver leads to a fate switch from a VMH neuronal phenotype to a hypothalamic but non-VMH identity, suggesting that Rax is a selector gene for VMH cellular fates. Finally, the broader elimination of Rax throughout ARC/VMH progenitors using Six3∷Cre leads to a severe loss of both VMH and ARC cellular phenotypes, demonstrating a role for Rax in both VMH and ARC fate specification. Combined, our study illustrates that Rax is required in ARC/VMH progenitors to specify neuronal phenotypes within this hypothalamic brain region. Rax thus provides a molecular entry point for further study of the ontology and establishment of hypothalamic feeding circuits.