Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux

Congenital anomalies of the kidney and urinary tract (CAKUT) include vesicoureteral reflux (VUR). VUR is a complex, genetically heterogeneous developmental disorder characterized by the retrograde flow of urine from the bladder into the ureter and is associated with reflux nephropathy, the cause of 15% of end-stage renal disease in children and young adults. We investigated a man with a de novo translocation, 46,X,t(Y;3)(p11;p12)dn, who exhibits multiple congenital abnormalities, including severe bilateral VUR with ureterovesical junction defects. This translocation disrupts ROBO2, which encodes a transmembrane receptor for SLIT ligand, and produces dominant-negative ROBO2 proteins that abrogate SLIT-ROBO signaling in vitro. In addition, we identified two novel ROBO2 intracellular missense variants that segregate with CAKUT and VUR in two unrelated families. Adult heterozygous and mosaic mutant mice with reduced Robo2 gene dosage also exhibit striking CAKUT-VUR phenotypes. Collectively, these results implicate the SLIT-ROBO signaling pathway in the pathogenesis of a subset of human VUR

Vascular and neuronal development: Intersecting parallelisms and rossroads

Two key events during evolution allowed vertebrates to develop specialized tissues able to perform complex tasks: the formation of a highly branched vascular system ensuring that all tissues receive adequate blood supply, and the development of a nervous system in which nerves branches to transmit electrical signal to peripheral organs. Both networks are laid down in a complex and stereotyped manner, which is tightly controlled by a series of shared developmental cues. Vessels and nerves use similar signals and principles to grow, differentiate and navigate toward their final targets. Moreover, the vascular and the nervous system cross-talk and, when deregulated, they contribute to medically relevant diseases. The emerging evidence that both systems share several molecular pathways not only provides an important link between vascular biology and neuroscience, but also promises to accelerate the discovery of new pathogenetic insights and therapeutic strategies