Congenital anomalies of the urinary tract are a significant cause of morbidity in infancy, and many congenital anomalies are linked to ureter development; however, the mechanism by which congenital anomalies control ureter development remains unknown. The loss of Robo2 can cause ureter defects and vesicoureteral reflux. However, how Robo2 impacts ureter development is unclear. We found that ROBO2 is expressed in the common nephric duct (CND) and primitive bladder, and impacts CND migration and fusion with the primitive bladder via its novel binding partner retinaldehyde dehydrogenase-2 (RALDH2). Delayed apoptosis that is due to the failure of CND fusion with the primitive bladder in the Robo2^-/-embryo results in an abnormal ureter connection to the CND, which is required for ureter development. We define a novel pathway in which the CND is remodeled by ROBO2 and retinoic acid rescued the ureter anomalies in the Robo2^-/-embryo. These findings may be relevant to diverse disease conditions that are associated with altered signaling in the primitive bladder.

泌尿系先天性异常是婴儿发病的重要原因，许多先天性异常与输尿管发育有关。然而，先天性异常控制输尿管发育的机制仍然未知。Robo2的丢失会导致输尿管缺陷和膀胱输尿管反流。但是，Robo2如何影响输尿管发育尚不清楚。我们发现，ROBO2在肾总管（CND）和原始膀胱中表达，并通过其新的结合伴侣视黄醛脱氢酶2（RALDH2）影响CND迁移和与原始膀胱融合。CND与Robo2 ^-/-原始膀胱融合失败导致细胞凋亡延迟胚胎导致输尿管与CND的连接异常，这是输尿管发育所必需的。我们定义了一种新的途径，其中CND被ROBO2重塑，视黄酸挽救了Robo2 ^-/-胚胎中的输尿管异常。这些发现可能与与原始膀胱信号改变有关的多种疾病状况有关。