PDF(Pubmed)
Abstract：
Caudal developmental defects, including caudal regression, caudal dysgenesis and sirenomelia, are devastating conditions affecting the skeletal, nervous, digestive, reproductive and excretory systems. Defects in mesodermal migration and blood supply to the caudal region have been identified as possible causes of caudal developmental defects, but neither satisfactorily explains the structural malformations in all three germ layers. Here, we describe caudal developmental defects in transmembrane protein 132a (Tmem132a) mutant mice, including skeletal, posterior neural tube closure, genitourinary tract and hindgut defects. We show that, in Tmem132a mutant embryos, visceral endoderm fails to be excluded from the medial region of early hindgut, leading directly to the loss or malformation of cloaca-derived genitourinary and gastrointestinal structures, and indirectly to the neural tube and kidney/ureter defects. We find that TMEM132A mediates intercellular interaction, and physically interacts with planar cell polarity (PCP) regulators CELSR1 and FZD6. Genetically, Tmem132a regulates neural tube closure synergistically with another PCP regulator Vangl2. In summary, we have identified Tmem132a as a new regulator of PCP, and hindgut malformation as the underlying cause of developmental defects in multiple caudal structures.
摘要：
尾端发育缺陷,包括尾部回归，尾发育不全和sirenomelia,是影响骨骼的毁灭性条件，紧张,消化性,生殖系统和排泄系统。中胚层迁移和向尾区供血的缺陷已被确定为尾区发育缺陷的可能原因，但都不能令人满意地解释所有三个胚层的结构畸形。在这里，我们描述了跨膜蛋白132a（Tmem132a）突变小鼠的尾发育缺陷，包括骨骼,后神经管闭合术,泌尿生殖道和后肠缺陷。我们表明，在Tmem132a突变胚胎中，内脏内胚层未能被排除在早期后肠的内侧区域，直接导致泄殖腔来源的泌尿生殖系统和胃肠道结构的丢失或畸形，和间接神经管和肾/输尿管缺陷。我们发现TMEM132A介导细胞间相互作用，并与平面电池极性（PCP）调节剂CELSR1和FZD6物理相互作用。基因上,Tmem132a与另一个PCP调节剂Vangl2协同调节神经管闭合。总之,我们已经确定Tmem132a是PCP的新调节剂，和后肠畸形是多个尾部结构发育缺陷的根本原因。
