A Grhl2-dependent gene network controls trophoblast branching morphogenesis
A Grhl2-dependent gene network controls trophoblast branching morphogenesis
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DOI：
10.1242/dev.113829
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发表时间：
2015-03
期刊：
影响因子：
4.6
通讯作者：
K. Walentin;C. Hinze;Max Werth;N. Haase;S. Varma;R. Morell;Annekatrin Aue;Elisabeth Pötschke;D. Warburton;A. Qiu;J. Barasch;B. Purfürst;C. Dieterich;E. Popova;M. Bader;R. Dechend;A. Staff;Zeliha Yesim Yurtdas;E. Kilic;K. Schmidt-Ott
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文献类型：
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作者：
K. Walentin;C. Hinze;Max Werth;N. Haase;S. Varma;R. Morell;Annekatrin Aue;Elisabeth Pötschke;D. Warburton;A. Qiu;J. Barasch;B. Purfürst;C. Dieterich;E. Popova;M. Bader;R. Dechend;A. Staff;Zeliha Yesim Yurtdas;E. Kilic;K. Schmidt-Ott
健康的胎盘发育对生殖成功至关重要;胎儿-母体界面的失败导致先兆子痫和宫内生长迟缓。我们发现，颗粒头样2（GRHL 2），CP 2型转录因子，是高度表达的绒毛膜滋养层细胞，包括基底绒毛膜滋养层（BCT）细胞位于绒毛尿囊界面在小鼠胎盘。胎盘从Grhl 2缺陷小鼠胚胎显示缺陷的BCT细胞极性和基底膜完整性的绒毛尿囊界面，以及严重破坏的迷宫分支形态发生。选择性Grhl 2失活只在上胚层衍生的细胞拯救所有的胎盘缺陷，但表型复制的胚胎内缺陷中观察到的全球Grhl 2缺陷，这意味着重要的Grhl 2活性滋养外胚层衍生的细胞。ChIP-seq在胎盘组织中鉴定了5282个GRHL 2结合位点。通过将这些数据与胎盘基因表达谱相结合，我们确定了直接和间接的Grhl 2靶点，并发现与Grhl 2 −/−胎盘中下调的基因相邻的GRHL 2结合显著富集，该基因编码胎盘发育和上皮形态发生的已知调节因子。这些基因包括编码丝氨酸蛋白酶抑制剂Kunitz 1型（Spint 1）的基因，该基因调节BCT细胞的完整性和迷路形成。在人胎盘中，我们发现鼠GRHL 2及其靶点的人直系同源物显示出协同调节，并且在滋养层细胞中以与小鼠胎盘相似的结构域表达。我们的数据表明，一个保守的Grhl 2协调的基因网络控制滋养层分支形态发生，从而促进发展的胎儿-母体交换的网站。这可能与胎盘功能障碍相关的综合征有关。总结：Grhl 2是Grainyhead转录因子家族的成员，控制着滋养层基因程序，该程序对于小鼠胎盘迷路的正常发育至关重要。
Healthy placental development is essential for reproductive success; failure of the feto-maternal interface results in pre-eclampsia and intrauterine growth retardation. We found that grainyhead-like 2 (GRHL2), a CP2-type transcription factor, is highly expressed in chorionic trophoblast cells, including basal chorionic trophoblast (BCT) cells located at the chorioallantoic interface in murine placentas. Placentas from Grhl2-deficient mouse embryos displayed defects in BCT cell polarity and basement membrane integrity at the chorioallantoic interface, as well as a severe disruption of labyrinth branching morphogenesis. Selective Grhl2 inactivation only in epiblast-derived cells rescued all placental defects but phenocopied intraembryonic defects observed in global Grhl2 deficiency, implying the importance of Grhl2 activity in trophectoderm-derived cells. ChIP-seq identified 5282 GRHL2 binding sites in placental tissue. By integrating these data with placental gene expression profiles, we identified direct and indirect Grhl2 targets and found a marked enrichment of GRHL2 binding adjacent to genes downregulated in Grhl2−/− placentas, which encoded known regulators of placental development and epithelial morphogenesis. These genes included that encoding the serine protease inhibitor Kunitz type 1 (Spint1), which regulates BCT cell integrity and labyrinth formation. In human placenta, we found that human orthologs of murine GRHL2 and its targets displayed co-regulation and were expressed in trophoblast cells in a similar domain as in mouse placenta. Our data indicate that a conserved Grhl2-coordinated gene network controls trophoblast branching morphogenesis, thereby facilitating development of the site of feto-maternal exchange. This might have implications for syndromes related to placental dysfunction. Summary: Grhl2, a member of the Grainyhead family of transcription factors, controls a trophoblast gene program that is essential for normal development of the mouse placental labyrinth.