The neonatal ventromedial hypothalamus transcriptome reveals novel markers with spatially distinct patterning
The neonatal ventromedial hypothalamus transcriptome reveals novel markers with spatially distinct patterning
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DOI：
10.1523/jneurosci.2858-07.2007
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发表时间：
2007-12-12
影响因子：
5.3
通讯作者：
Ingraham, Holly A.
中科院分区：
文献类型：
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作者：
Kurrasch, Deborah M.;Cheung, Clement C.;Ingraham, Holly A.
下丘脑腹内侧（VMH）是一个独特的形态核，参与进食、恐惧、体温调节和性活动。从本质上讲，这些先天反应背后的VMH回路是如何发展的尚不清楚，部分原因是VMH在细胞和分子水平上仍然没有明确的定义。具体来说，缺乏细胞类型特异性的遗传标记来识别神经元亚群并操纵体内的发育和信号传导。利用基因图谱，我们现在鉴定出在新生儿（出生后第0天）小鼠VMH组织中高度富集的类似200个基因。通过真实或虚拟的实验（Allen Brain Atlas; http:// www.brain-map.org）对这些脑后血管瘤标记物进行分析，发现在新形成的脑后血管瘤中存在明显的区域模式。最重要的新生儿标志物包括转录调控因子，如Vgll2、SF-1、Sox14、Satb2、Fezf1、Dax1、Nkx2-2和COUP-TFII，但有趣的是，最高表达的VMH转录因子，转录共调控因子Vgll2，在老年动物中完全不存在。斑马鱼敲除实验和细胞研究的共同结果表明，这些VMH标记的一个子集对下丘脑发育很重要，并且将位于SF-1的下游，SF-1是正常VMH分化的关键因素。我们发现，至少有一种VMH标记物，即富含at的结合蛋白Satb2，在出生后第0天对瘦素信号（Lep(ob/ob)）的缺失有反应，但在成人中没有反应，这表明一些VMH转录程序可能受到胎儿或出生后早期环境的影响。我们的研究描述了这个全面的“VMH转录组”，为进一步探索先天神经内分泌行为反应的遗传基础提供了一个新的分子工具包。
The ventromedial hypothalamus (VMH) is a distinct morphological nucleus involved in feeding, fear, thermoregulation, and sexual activity. It is essentially unknown how VMH circuits underlying these innate responses develop, in part because the VMH remains poorly defined at a cellular and molecular level. Specifically, there is a paucity of cell-type-specific genetic markers with which to identify neuronal subgroups and manipulate development and signaling in vivo. Using gene profiling, we now identify similar to 200 genes highly enriched in neonatal ( postnatal day 0) mouse VMH tissue. Analyses of these VMH markers by real or virtual (Allen Brain Atlas; http:// www.brain-map.org) experiments revealed distinct regional patterning within the newly formed VMH. Top neonatal markers include transcriptional regulators such as Vgll2, SF-1, Sox14, Satb2, Fezf1, Dax1, Nkx2-2, and COUP-TFII, but interestingly, the highest expressed VMH transcript, the transcriptional coregulator Vgll2, is completely absent in older animals. Collective results from zebrafish knockdown experiments and from cellular studies suggest that a subset of these VMH markers will be important for hypothalamic development and will be downstream of SF-1, a critical factor for normal VMH differentiation. We show that at least one VMH marker, the AT-rich binding protein Satb2, was responsive to the loss of leptin signaling (Lep(ob/ob)) at postnatal day 0 but not in the adult, suggesting that some VMH transcriptional programs might be influenced by fetal or early postnatal environments. Our study describing this comprehensive "VMH transcriptome" provides a novel molecular toolkit to probe further the genetic basis of innate neuroendocrine behavioral responses.