Abnormal Paraventricular Nucleus of Hypothalamus and Growth Retardation Associated with Loss of Nuclear Receptor Gene COUP-TFII.
Abnormal Paraventricular Nucleus of Hypothalamus and Growth Retardation Associated with Loss of Nuclear Receptor Gene COUP-TFII.
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核受体基因 COUP-TFII 缺失相关的下丘脑室旁核异常和生长迟缓
DOI：
10.1038/s41598-017-05682-6
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发表时间：
2017-07-13
影响因子：
4.6
通讯作者：
Tang K
中科院分区：
文献类型：
--
作者：
Feng S;Xing C;Shen T;Qiao Y;Wang R;Chen J;Liao J;Lu Z;Yang X;Abd-Allah SM;Li J;Jing N;Tang K
下丘脑室旁核在能量平衡和胎儿生长发育中起重要作用。然而，其形成和功能的分子机制尚未明确阐明。编码核受体的人COUP-TFII基因中的各种突变导致生长迟缓、先天性疝气和先天性心脏缺陷。在这里，我们表明，COUP-TFII基因表达在发育中的小鼠下丘脑。腹侧前脑特异性RXCre/+; COUP-TFIIF/F突变小鼠表现出生长迟缓。在COUP-TFII突变体中，下丘脑室旁核的发育受到损害，主要是因为Brn 2+神经元的凋亡和误迁移增加。此外，突变体的垂体前叶发育不良，血细胞聚集，垂体后叶萎缩，缺乏AVP/OT神经元的支配，表明下丘脑-垂体轴的形成失败。机制研究表明，突变胚胎中Bdnf和Nrp 1基因的表达减少，Bdnf是COUP-TFII蛋白的直接下游靶点。因此，我们的研究结果提供了一个新的功能验证，COUP-TFII基因促进Bdnf和Nrp 1基因的表达，以确保适当的形态发生的下丘脑-垂体轴，特别是下丘脑室旁核，并防止生长迟缓。
The paraventricular nucleus of hypothalamus plays important roles in the regulation of energy balance and fetal growth. However, the molecular mechanisms underlying its formation and function have not been clearly elucidated. Various mutations in the human COUP-TFII gene, which encodes a nuclear receptor, result in growth retardation, congenital diaphragmatic hernia and congenital heart defects. Here, we show that COUP-TFII gene is expressed in the developing hypothalamus in mouse. The ventral forebrain-specific RXCre/+; COUP-TFIIF/F mutant mice display growth retardation. The development of the paraventricular nucleus of hypothalamus is compromised in the COUP-TFII mutant mainly because of increased apoptosis and mis-migration of the Brn2+ neurons. Moreover, hypoplastic anterior pituitary with blood cell clusters and shrunken posterior pituitary lacking AVP/OT neuron innervations are observed in the mutant, indicating the failure of formation of the hypothalamic-pituitary axis. Mechanistic studies show that the expression of Bdnf and Nrp1 genes is reduced in the mutant embryo, and that Bdnf is a direct downstream target of the COUP-TFII protein. Thus, our findings provide a novel functional validation that COUP-TFII gene promotes the expression of Bdnf and Nrp1 genes to ensure the appropriate morphogenesis of the hypothalamic-pituitary axis, especially the paraventricular nucleus of hypothalamus, and to prevent growth retardation.
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影响因子：
10.5
作者：
Acampora, D;Postiglione, MP;Simeone, A
通讯作者：
Simeone, A
影响因子：
64.5
作者：
Gautron L;Elmquist JK;Williams KW
通讯作者：
Williams KW
影响因子：
2
作者：
Arrington, Cammon B.;Bleyl, Steven B.;Matsunami, Nori;Bowles, Neil E.;Leppert, Tami I.;Demarest, Bradley L.;Osborne, Karen;Yoder, Bradley A.;Byrne, Janice L.;Schiffman, Joshua D.;Null, Donald M.;DiGeronimo, Robert;Rollins, Michael;Faix, Roger;Comstock, Jessica;Camp, Nicola J.;Leppert, Mark F.;Yost, H. Joseph;Brunelli, Luca
通讯作者：
Brunelli, Luca
影响因子：
2
作者：
High, Frances A.;Bhayani, Pooja;Wilson, Jay M.;Bult, Carol J.;Donahoe, Patricia K.;Longoni, Mauro
通讯作者：
Longoni, Mauro
影响因子：
64.8
作者：
Fan, W;Boston, BA;Cone, RD
通讯作者：
Cone, RD