Abstract
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.
Highlights
The mammalian kidney contains nephrons, comprising glomeruli and tubules, joined to ureteric bud–derived collecting ducts
Ureteric branching in the early metanephros of wild-type mice Metanephric kidneys were harvested from wild-type mice at embryonic day (E)13.5 and whole-mount immunostaining for calbindin-D28K was undertaken[18,19] to visualize the ureteric tree using optical projection tomography (OPT).[20]
In early kidney development it is required for ureteric tree growth, whereas later in gestation it prevents tubule overgrowth in association with orientation of mitosis along the longitudinal axis of kidney tubules
Summary
The mammalian kidney contains nephrons, comprising glomeruli and tubules, joined to ureteric bud–derived collecting ducts. The first branch point of the bud within the just-formed metanephros defines the kidney’s rostral and caudal domains, and a mixture of predominantly dichotomous branching and some trichotomous branching establishes the organ’s bean shape.[3] The second growth phase is dominated by nephrons that differentiate into podocytes, proximal tubules, and loops of Henle, together with the continued branching of the ureteric tree in the outer cortex. PCP genes have been implicated in kidney differentiation, especially controlling tubular diameter, partly through orienting cell divisions.[11,12,13] We reported that the initiation of the ureteric bud was normal in homozygous mutant Vangl[2] embryos, subsequent ureteric bud branching within the metanephros was defective.[14] we[14]
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