Departments of Internal Medicine (Renal Division), Pathology and Immunology; Washington University School of Medicine; St. Louis, MO USA.
Organogenesis. 2009 Oct;5(4):177-90. doi: 10.4161/org.5.4.10048.
Signaling pathways that are activated upon interaction of glial cell-line derived neurotrophic factor (Gdnf), its coreceptor Gfra1, and receptor tyrosine kinase Ret are critical for kidney development and ureter maturation. Outside the kidney, this pathway is implicated in a number of congenital diseases including Hirschsprung disease (intestinal aganglionosis, HSCR) and hereditary cancer syndromes (MEN 2). Total lack of Gdnf, Gfra1 or Ret in mice results in perinatal lethality due to bilateral renal agenesis or aplasia. In humans, RET mutations have been identified in a spectrum of congenital malformations involving the RET axis including isolated HSCR, isolated congenital anomalies of kidney or urinary tract (CAKUT), or CAKUT and HSCR together. The molecular basis for these pleiotropic effects of RET has just begun to be unraveled. In an effort to delineate the pathogenetic mechanisms that underlie these congenital malformations, we and others have characterized Ret's role in early kidney and urinary system development. Here we present a brief overview of the "many faces" of Ret dysfunction in kidney with particular emphasis on Ret's signaling specificity and intergenic interactions that confer normal urinary system development.
胶质细胞源性神经营养因子（GDNF）与其核心受体 Gfra1 和受体酪氨酸激酶 Ret 相互作用后被激活的信号通路对于肾脏发育和输尿管成熟至关重要。在肾脏外，该通路与许多先天性疾病有关，包括先天性巨结肠（肠无神经节，HSCR）和遗传性癌症综合征（MEN 2）。Gdnf、Gfra1 或 Ret 在小鼠中的完全缺失会导致围产期死亡，因为双侧肾脏发育不全或发育不良。在人类中，已经在涉及 RET 轴的一系列先天性畸形中鉴定出 RET 突变，包括孤立性 HSCR、孤立性肾脏或泌尿系统先天性异常（CAKUT），或 CAKUT 和 HSCR 一起。RET 这些多效性效应的分子基础才刚刚开始被揭示。为了阐明这些先天性畸形的发病机制，我们和其他研究人员已经描述了 Ret 在早期肾脏和泌尿系统发育中的作用。在这里，我们简要概述了 Ret 在肾脏中的“多面性”功能障碍，特别强调了 Ret 的信号特异性和基因间相互作用，这些特异性和相互作用赋予了正常的泌尿系统发育。
