Signaling during mammalian urogential-anorectal develop

在胚胎发育过程中，泌尿生殖-肛肠结构的畸形是人类常见的先天缺陷。例如，尿道下裂是由于尿道上皮细胞不能形成管状而引起的，大约每320个男婴中就有1个发生尿道下裂。控制泌尿生殖和肛肠结构发育的基因、蛋白质和细胞信号网络尚不清楚。Eph家族的受体酪氨酸激酶及其膜锚定的ephrin配体是高度保守的分子，在多种细胞-细胞识别事件中起作用，包括神经系统中轴突寻路、神经嵴细胞迁移和血管组织中所需的识别事件。初步数据显示，某些Eph受体和ephrin基因靶向突变的小鼠表现为尿道下裂和泄殖腔和泄殖腔膜的延迟分隔，这是泌尿生殖-肛肠发育异常中线融合的两种常见失败特征。为了更详细地探索这些初步发现，提出了三个具体目标：1)充分表征在Eph和ephrin突变小鼠中观察到的异常泌尿生殖-肛肠发育；2)通过体外和体内实验研究和干扰泌尿生殖系统中Eph/ephrin信号的活性；3)通过记录Eph受体和ephrin分子的表达，以及筛选先天性尿道下裂和其他后肠异常个体中ephrin基因的突变，来描述Eph受体和ephrin在人类泌尿生殖-肛肠发育中的重要性。通过结合小鼠分子遗传学，生化分析和临床研究的力量，该合作研究项目的总体目标是详细描述哺乳动物泌尿生殖-肛肠发育中利用的细胞-细胞信号转导事件。

Malformations of urogenital-anorectal structures during embryonic development are frequently observed birth defects in humans. For instance, hypospadias, which is due to a failure of the urethral epithelial cells to tubularize, occurs in approximately 1 out of every 320 male births. The genes, proteins, and cell signaling networks that control development of urogenital and anorectal structures are poorly understood. The Eph family of receptor tyrosine kinases and their membrane- anchored ephrin ligands are highly conserved molecules that function in diverse cell-cell recognition events, including those required for axon pathfinding in the nervous system, in migration of neural crest cells and in vascular organization. Preliminary data is provided that show gene-targeted mice mutant for certain Eph receptors and ephrins display hypospadias and delayed septation of the cloaca and cloacal membrane, two common failures in midline fusion characteristic of abnormal urogenital-anorectal development. To explore these preliminary findings in greater detail, three specific aims are proposed: 1) To fully characterize the abnormal urogenital-anorectal development observed in the Eph and ephrin mutant mice; 2) To study and perturb the activities of Eph/ephrin signals in the urogenital system by developing in vitro and in vivo assays; and 3) To delineate the importance of Eph receptors and ephrins in human urogenital-anorectal development by documenting the expression of these molecules and by screening for mutations in ephrin genes in individuals born with hypospadias and other hindgut abnormalities. By combining the powers of mouse molecular genetics, biochemical analysis and clinical-based studies, the overall goal of this collaborative research project is to characterize in detail the cell-cell signal transduction events that are utilized in mammalian urogenital-anorectal development.