The mammalian kidney contains nephrons comprising glomeruli and tubules joined to ureteric bud–derived collecting ducts. It has a characteristic bean-like shape, with near-complete rostrocaudal symmetry around the hilum. Here we show that Celsr1, a planar cell polarity (PCP) gene implicated in neural tube morphogenesis, is required for ureteric tree growth in early development and later in gestation prevents tubule overgrowth. We also found an interaction between Celsr1 and Vangl2 (another PCP gene) in ureteric tree growth, most marked in the caudal compartment of the kidneys from compound heterozygous mutant mice with a stunted rump. Furthermore, these genes together are required for the maturation of glomeruli. Interestingly, we demonstrated patients with CELSR1 mutations and spina bifida can have significant renal malformations. Thus, PCP genes are important in mammalian kidney development and have an unexpected role in rostrocaudal patterning during organogenesis.
Bibliographical noteFunding Information:
We thank Dr. Ian Smyth (Monash University) for providing Tree Surveyor software, UCL Biological Services for their assistance with animal experiments, and both Dr. Charlotte Dean (Imperial College London) and Professor Andrew Copp (UCL Great Ormond Street Institute of Child Health) for helpful discussions regarding this work. This work was supported by a PhD studentship from Kids Kidney Research (to EP and DAL), a UCL Bogue Research Fellowship (to HLB), a Wellcome Trust Postdoctoral Training Fellowship for MB/PhD graduates (grant no. 095949/Z/11/Z to EP), a Kidney Research UK Senior Non-Clinical Fellowship (grant no. SF1/2008 to DAL), a Medical Research Council New Investigator Award (grant no. MR/J003638/1 to DAL), and the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. ASW acknowledges support from the Medical Research Council (project grant no. MR/L002744/1) and the Manchester Biomedial Research Centre and the Manchester Academic Health Science Centre. VP and PI acknowledge support from the O’Brien Kidney Center at University of Texas Southwestern Medical Center (grant no. NIH P30-DK079328).
© 2016 International Society of Nephrology
- kidney development
- planar cell polarity
- renal malformations
- rostrocaudal patterning
- ureteric branching