Bidirectional signaling mediated by ephrin-B2 and EphB2 controls urorectal development
Bidirectional signaling mediated by ephrin-B2 and EphB2 controls urorectal development
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DOI：
10.1016/j.ydbio.2004.03.027
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发表时间：
2004-07-15
影响因子：
2.7
通讯作者：
Henkemeyer, M
中科院分区：
文献类型：
--
作者：
Dravis, C;Yokoyama, N;Henkemeyer, M
不完全尿道小管化（尿道下裂）和肛门直肠畸形是两种常见的和知之甚少的出生缺陷，影响极端尾部中线的人类胚胎。我们现在表明，在发育中的神经系统，即肝配蛋白-B2和肝配蛋白受体EphB 2和EphB 3，适当的轴突寻路必不可少的细胞表面分子，也发挥了重要作用的细胞粘附事件，使尿道和分区的泌尿道和消化道。携带突变基因的小鼠会破坏这些分子的双向信号，从而导致严重的尿道下裂和原始泄殖腔中线融合不完全。我们进一步表明，动物完全缺乏肝配蛋白-B2反向信号提出了一个完全渗透失败的泄殖腔分隔。这会导致严重的肛门直肠畸形，其特征是最末端的后肠（直肠）缺失，并在膀胱底部形成异常连接肠道和尿道的瘘管。与这些尾部重塑事件中正向和反向信号传导的明显必要条件一致，EphB 2和ephrin-B2在融合的尿道/泄殖腔内胚层和下面的尿直肠隔膜的外侧中胚层中的中线处共表达，所述外侧中胚层随着泄殖腔隔膜向尾部中线迁移。因此，我们的数据表明，B-亚类Eph和肝配蛋白分子在这些临床上重要的中线细胞-细胞粘附和融合事件中发挥重要作用。(C)2004年爱思唯尔公司All rights reserved.
Incomplete urethral tubularization (hypospadias) and anorectal abnormalities are two common and poorly understood birth defects that affect the extreme caudal midline of the human embryo. We now show that cell surface molecules essential for proper axon pathfinding in the developing nervous system, namely ephrin-B2 and the ephrin receptors EphB2 and EphB3, also play major roles in cell adhesion events that tubularize the urethra and partition the urinary and alimentary tracts. Mice carrying mutations which disrupt the bidirectional signals that these molecules transduce develop with variably penetrant severe hypospadias and incomplete midline fusion of the primitive cloaca. We further show that animals completely lacking ephrin-B2 reverse signaling present a fully penetrant failure in cloacal septation. This results in severe anorectal malformations characterized by an absence of the terminal-most hindgut (rectum) and formation of a fistula that aberrantly connects the intestines to the urethra at the base of the bladder. Consistent with an apparent requisite for both forward and reverse signaling in these caudal remodeling events, EphB2 and ephrin-B2 are coexpressed at the midline in the fusing urethral/cloacal endoderm and underlying lateral mesoderm of the urorectal septum that migrates toward the caudal midline as the cloaca septates. Our data thus indicate that B-subclass Eph and ephrin molecules play an important role in these clinically significant midline cell-cell adhesion and fusion events. (C) 2004 Elsevier Inc. All rights reserved.