Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
Dev Cell. 2013 Sep 30;26(6):629-44. doi: 10.1016/j.devcel.2013.07.019.
A critical aspect of gut morphogenesis is initiation of a leftward tilt, and failure to do so leads to gut malrotation and volvulus. The direction of tilt is specified by asymmetric cell behaviors within the dorsal mesentery (DM), which suspends the gut tube, and is downstream of Pitx2, the key transcription factor responsible for the transfer of left-right (L-R) information from early gastrulation to morphogenesis. Although Pitx2 is a master regulator of L-R organ development, its cellular targets that drive asymmetric morphogenesis are not known. Using laser microdissection and targeted gene misexpression in the chicken DM, we show that Pitx2-specific effectors mediate Wnt signaling to activate the formin Daam2, a key Wnt effector and itself a Pitx2 target, linking actin dynamics to cadherin-based junctions to ultimately generate asymmetric cell behaviors. Our work highlights how integration of two conserved cascades may be the ultimate force through which Pitx2 sculpts L-R organs.
肠道形态发生的一个关键方面是启动向左倾斜，如果不能这样做，就会导致肠道旋转不良和扭转。倾斜的方向是由悬挂肠管的背系膜（DM）内不对称细胞行为决定的，而背系膜位于负责将左右（L-R）信息从早期原肠胚传递到形态发生的关键转录因子 Pitx2 的下游。虽然 Pitx2 是 L-R 器官发育的主要调节因子，但驱动不对称形态发生的细胞靶标尚不清楚。我们使用鸡 DM 中的激光显微切割和靶向基因表达错误，表明 Pitx2 特异性效应物介导 Wnt 信号激活形成素 Daam2，形成素 Daam2 是 Wnt 效应物的关键因子，本身也是 Pitx2 的靶标，将肌动蛋白动力学与基于钙粘蛋白的连接连接起来，最终产生不对称的细胞行为。我们的工作强调了两个保守级联如何整合可能是 Pitx2 塑造 L-R 器官的最终力量。
