Abstract
Mechanisms controlling ureter lenght and the position of the kidney are poorly understood. Glial cell-line derived neurotrophic factor (GDNF) induced RET signaling is critical for ureteric bud outgrowth, but the function of endogenous GDNF in further renal differentiation and urogenital system development remains discursive. Here we analyzed mice where 3′ untranslated region (UTR) of GDNF is replaced with sequence less responsive to microRNA-mediated regulation, leading to increased GDNF expression specifically in cells naturally transcribing Gdnf. We demonstrate that increased Gdnf leads to short ureters in kidneys located in an abnormally caudal position thus resembling human pelvic kidneys. High GDNF levels expand collecting ductal progenitors at the expense of ureteric trunk elongation and result in expanded tip and short trunk phenotype due to changes in cell cycle length and progenitor motility. MEK-inhibition rescues these defects suggesting that MAPK-activity mediates GDNF’s effects on progenitors. Moreover, Gdnf hyper mice are infertile likely due to effects of excess GDNF on distal ureter remodeling. Our findings suggest that dysregulation of GDNF levels, for example via alterations in 3′UTR, may account for a subset of congenital anomalies of the kidney and urinary tract (CAKUT) and/or congenital infertility cases in humans and pave way to future studies.
Highlights
Congenital anomalies of the kidney and urinary tract (CAKUT) are common birth defects affecting around 1% of live births, and causing most cases of the chronic kidney disease in children[1]
At E10.5, the nephric duct (ND) was connected to the cloaca in both control and Gdnf hyper/hyper embryos but the connecting segment of ND itself was dilated in the Gdnf hyper/hyper embryos (Fig. 1A,B)
We report that Glial cellline derived neurotrophic factor (GDNF) levels, as regulated by its functional 3′untranslated region (UTR), define ureter length and thereby delineate the position of the kidneys in abdominal cavity
Summary
Congenital anomalies of the kidney and urinary tract (CAKUT) are common birth defects affecting around 1% of live births, and causing most cases of the chronic kidney disease in children[1]. CAKUT covers a wide range of malformations that derive from deficiencies in embryonic kidney and lower urinary tract development, including obstruction of ureteropelvic junction, renal dysplasia, hydro-, ectopic and short ureters. Genetic causes for these malformations remain largely unknown despite the extensive sequencing efforts in gene coding regions[2]. Proper positioning and timing of ND connection to the cloaca are important steps for the later development and function of the kidney and rest of the urogenital system. With UB branching begins the distal ureter maturation, which remodels the most caudal segment of ND, called the common ND. The regulation of distal ureter remodeling is beginning to emerge[15], but how ureter length and anatomical positioning of urogenital organs occur are less well understood
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