Signaling during mammalian urogenital-anorectal develop

胚胎发育过程中泌尿生殖-肛门直肠结构畸形是人类常见的出生缺陷。 例如，尿道下裂，这是由于尿道上皮细胞未能管状化，发生在大约每320名男性出生1。 控制泌尿生殖和肛门直肠结构发育的基因、蛋白质和细胞信号网络知之甚少。 受体酪氨酸激酶的Eph家族和它们的膜锚定肝配蛋白配体是高度保守的分子，其在不同的细胞-细胞识别事件中起作用，包括神经系统中轴突寻路、神经嵴细胞的迁移和血管组织中所需的那些。 提供的初步数据显示，某些Eph受体和肝配蛋白的基因靶向小鼠突变体显示尿道下裂和泄殖腔和泄殖腔膜的延迟分隔，这是异常泌尿生殖器-肛门直肠发育的中线融合特征的两种常见失败。 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系统-肛门直肠发育：2）通过开发体外和体内测定来研究和干扰Eph/ephrin信号在泌尿生殖系统中的活性;阐明Eph受体和ephrin在人类泌尿生殖系统中的重要性。通过记录这些分子的表达，并通过筛查先天性尿道下裂个体中ephrin基因的突变，其他后肠异常 通过结合小鼠分子遗传学，生化分析和临床研究的力量，这个合作研究项目的总体目标是详细描述哺乳动物泌尿生殖系统肛门直肠发育中使用的细胞-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.