Loss of function of mouse Pax-Interacting Protein 1-associated glutamate rich protein 1a (Pagr1a) leads to reduced Bmp2 expression and defects in chorion and amnion development.
Loss of function of mouse Pax-Interacting Protein 1-associated glutamate rich protein 1a (Pagr1a) leads to reduced Bmp2 expression and defects in chorion and amnion development.
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DOI：
10.1002/dvdy.24125
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发表时间：
2014-07
期刊：
影响因子：
--
通讯作者：
Kuehn MR
中科院分区：
文献类型：
--
作者：
Kumar A;Lualdi M;Loncarek J;Cho YW;Lee JE;Ge K;Kuehn MR
人PAX相互作用蛋白1(PAXIP1)相关的谷氨酸富含蛋白1(PAGR1，也称为PA1)最初是由PAXIP1和组蛋白H3K4甲基转移酶MLL3和MLL4组成的复合体的一部分，表明它在表观基因调控中发挥作用。进一步的体外研究表明，在DNA损伤修复和转录中还有其他功能。然而，目前还缺乏对PAGR1功能的体内分析。在这里，我们发现同源的小鼠基因Pagr1a主要在胚胎外胚层和绒毛膜外胚层中表达，并且在原肠胚形成后在胚胎内部表达上调。具有Pagr1a胚系缺失的胚胎建立了前后轴，并显示出正常的神经外胚层、中胚层和内胚层图案，但不能发育到四到五体节阶段或经历轴向旋转。Pagr1a−/−胚胎还显示胚外组织发育异常，羊膜、绒毛和内脏卵黄囊出现缺陷。在分子水平上，Pagr1a−/−胚胎减少了骨形态发生蛋白2的表达，骨形态发生蛋白2是一种已知的胚胎外发育调节因子。小鼠Pagr1a功能的丧失会导致胚胎外发育缺陷，这可能至少部分是由于BMP信号改变，导致发育停滞。
Human PAX-Interacting Protein 1 (PAXIP1)-associated glutamate rich protein 1 (PAGR1, also known as PA1) originally was discovered as part of a complex containing PAXIP1 and histone H3K4 methyltransferases MLL3 and MLL4, suggesting a role in epigenetic gene regulation. Further in vitro studies suggested additional functions in DNA damage repair and transcription. However, in vivo analysis of PAGR1 function has been lacking. Here we show that expression of the cognate mouse gene Pagr1a is found predominately in the extraembryonic and chorionic ectoderm from pregastrulation stages and is up-regulated within the embryo proper after gastrulation. Embryos with a germ line deletion of Pagr1a establish the anterior–posterior axis, and show normal neuroectodermal, mesodermal, and endodermal patterning, but fail to develop beyond the four- to five-somite stage or to undergo axial rotation. Pagr1a−/− embryos also show abnormal development of extraembryonic tissues with defects seen in the amnion, chorion and visceral yolk sac. At the molecular level, Pagr1a−/− embryos have reduced expression of BMP2, a known regulator of extraembryonic development. Loss of mouse Pagr1a function leads to defective extraembryonic development, likely due at least in part to altered BMP signaling, contributing to developmental arrest.
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