Hartwig Sunny, Bridgewater Darren, Di Giovanni Valeria, Cain Jason, Mishina Yuji, Rosenblum Norman D
Division of Nephrology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada.
J Am Soc Nephrol. 2008 Jan;19(1):117-24. doi: 10.1681/ASN.2007010080.
The molecular signals that regulate growth and branching of the ureteric bud during formation of the renal collecting system are largely undefined. Members of the bone morphogenetic protein (BMP) family signal through the type I BMP receptor ALK3 to inhibit ureteric bud and collecting duct cell morphogenesis in vitro. We investigated the function of the BMP signaling pathway in vivo by generating a murine model of ALK3 deficiency restricted to the ureteric bud lineage (Alk3(UB-/-) mice). At the onset of branching morphogenesis, Alk3(UB-/-) kidneys are characterized by an abnormal primary (1 degrees ) ureteric bud branch pattern and an increased number of ureteric bud branches. However, during later stages of renal development, Alk3(UB-/-) kidneys have fewer ureteric bud branches and collecting ducts than wild-type kidneys. Postnatal Alk3(UB-/-) mice exhibit a dysplastic renal phenotype characterized by hypoplasia of the renal medulla, a decreased number of medullary collecting ducts, and abnormal expression of beta-catenin and c-MYC in medullary tubules. In summary, normal kidney development requires ALK3-dependent BMP signaling, which controls ureteric bud branching.
在肾集合系统形成过程中，调节输尿管芽生长和分支的分子信号在很大程度上尚不明确。骨形态发生蛋白（BMP）家族成员通过I型BMP受体ALK3发出信号，在体外抑制输尿管芽和集合管细胞的形态发生。我们通过构建一个仅限于输尿管芽谱系的ALK3缺陷小鼠模型（Alk3(UB-/-)小鼠）来研究BMP信号通路在体内的功能。在分支形态发生开始时，Alk3(UB-/-)小鼠的肾脏表现为初级（1°）输尿管芽分支模式异常以及输尿管芽分支数量增加。然而，在肾脏发育的后期阶段，Alk3(UB-/-)小鼠的肾脏输尿管芽分支和集合管比野生型小鼠的少。出生后的Alk3(UB-/-)小鼠表现出一种发育异常的肾脏表型，其特征为肾髓质发育不全、髓质集合管数量减少以及β-连环蛋白和c-MYC在髓质小管中的异常表达。总之，正常的肾脏发育需要依赖ALK3的BMP信号，该信号控制输尿管芽的分支。
