Cancer and Developmental Biology Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, Frederick, Maryland, United State of America.
Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, Frederick, Maryland, United State of America.
PLoS One. 2020 Apr 30;15(4):e0232025. doi: 10.1371/journal.pone.0232025. eCollection 2020.
The actin cytoskeleton plays a central role in establishing cell polarity and shape during embryonic morphogenesis. Daam1, a member of the Formin family of actin cytoskeleton regulators, is a Dvl2-binding protein that functions in the Wnt/Planar Cell Polarity (PCP) pathway. To examine the role of the Daam proteins in mammalian development, we generated Daam-deficient mice by gene targeting and found that Daam1, but not Daam2, is necessary for fetal survival. Embryonic development of Daam1 mutants was delayed most likely due to functional defects in the labyrinthine layer of the placenta. Examination of Daam2 and Daam1/2 double mutants revealed that Daam1 and Daam2 are functionally redundant during placental development. Of note, neural tube closure defects (NTD), which are observed in several mammalian PCP mutants, are not observed in Wnt5a or Daam1 single mutants, but arise in Daam1;Wnt5a double mutants. These findings demonstrate a unique function for Daam genes in placental development and are consistent with a role for Daam1 in the Wnt/PCP pathway in mammals.
肌动蛋白细胞骨架在胚胎形态发生过程中对建立细胞极性和形状起着核心作用。Daam1 是肌动蛋白细胞骨架调节剂 Formin 家族的成员，是 Dvl2 结合蛋白，在 Wnt/平面细胞极性 (PCP) 途径中发挥作用。为了研究 Daam 蛋白在哺乳动物发育中的作用，我们通过基因靶向生成了 Daam 缺陷型小鼠，并发现 Daam1（而非 Daam2）对于胎儿存活是必需的。Daam1 突变体的胚胎发育延迟很可能是由于胎盘迷路层的功能缺陷所致。对 Daam2 和 Daam1/2 双突变体的检查表明，在胎盘发育过程中，Daam1 和 Daam2 具有功能冗余性。值得注意的是，在几种哺乳动物 PCP 突变体中观察到的神经管闭合缺陷 (NTD) 在 Wnt5a 或 Daam1 单突变体中未观察到，但在 Daam1;Wnt5a 双突变体中观察到。这些发现表明 Daam 基因在胎盘发育中具有独特的功能，并且与 Daam1 在哺乳动物 Wnt/PCP 途径中的作用一致。
