Orquera Daniela P, Nasif Sofia, Low Malcolm J, Rubinstein Marcelo, de Souza Flávio S J
Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas, 1428 Buenos Aires, Argentina.
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48105, United States.
Dev Biol. 2016 Aug 1;416(1):212-224. doi: 10.1016/j.ydbio.2016.05.021. Epub 2016 May 19.
The hypothalamus is a region of the anterior forebrain that controls basic aspects of vertebrate physiology, but the genes involved in its development are still poorly understood. Here, we investigate the function of the homeobox gene Rax/Rx in early hypothalamic development using a conditional targeted inactivation strategy in the mouse. We found that lack of Rax expression prior to embryonic day 8.5 (E8.5) caused a general underdevelopment of the hypothalamic neuroepithelium, while inactivation at later timepoints had little effect. The early absence of Rax impaired neurogenesis and prevented the expression of molecular markers of the dorsomedial hypothalamus, including neuropeptides Proopiomelanocortin and Somatostatin. Interestingly, the expression domains of genes expressed in the ventromedial hypothalamus and infundibulum invaded dorsal hypothalamic territory, showing that Rax is needed for the proper dorsoventral patterning of the developing medial hypothalamus. The phenotypes caused by the early loss of Rax are similar to those of eliminating the expression of the morphogen Sonic hedgehog (Shh) specifically from the hypothalamus. Consistent with this similarity in phenotypes, we observed that Shh and Rax are coexpressed in the rostral forebrain at late head fold stages and that loss of Rax caused a downregulation of Shh expression in the dorsomedial portion of the hypothalamus.
下丘脑是前脑前部的一个区域，它控制着脊椎动物生理学的基本方面，但参与其发育的基因仍知之甚少。在这里，我们使用小鼠中的条件性靶向失活策略，研究同源框基因Rax/Rx在早期下丘脑发育中的功能。我们发现，在胚胎第8.5天（E8.5）之前缺乏Rax表达会导致下丘脑神经上皮普遍发育不全，而在后期时间点失活则影响很小。Rax的早期缺失会损害神经发生，并阻止下丘脑背内侧分子标记物的表达，包括神经肽阿黑皮素原和生长抑素。有趣的是，在下丘脑腹内侧和漏斗中表达的基因的表达域侵入了下丘脑背侧区域，这表明Rax是发育中的内侧下丘脑正常背腹模式形成所必需的。Rax早期缺失所导致的表型与特异性消除下丘脑形态发生素音猬因子（Shh）表达所导致的表型相似。与表型上的这种相似性一致，我们观察到Shh和Rax在头褶后期的前脑前端共同表达，并且Rax的缺失导致下丘脑背内侧部分Shh表达下调。
