Development of the urogenital system is regulated via the 3'UTR of GDNF.

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.

• Authors: Hao Li, Madis Jakobson, Roxana Ola, Yujuan Gui, Anmol Kumar, Petra Sipilä, Hannu Sariola, Satu Kuure, Jaan-Olle Andressoo
• Journal: Scientific reports (Sci Rep) Vol. 9 Issue 1 Pg. 5302 (03 28 2019) ISSN: 2045-2322 [Electronic] England
• PMID: 30923332 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3' Untranslated Regions
• Gdnf protein, mouse
• Glial Cell Line-Derived Neurotrophic Factor
• MicroRNAs

Topics

• 3' Untranslated Regions (genetics)
• Animals
• Apoptosis (genetics)
• Cell Cycle (genetics)
• Cell Movement (genetics)
• Disease Models, Animal
• Embryo, Mammalian
• Female
• Gene Expression Regulation, Developmental
• Glial Cell Line-Derived Neurotrophic Factor (genetics, metabolism)
• Humans
• Infertility (congenital, genetics, pathology)
• Kidney (abnormalities, embryology, pathology)
• Male
• Mice
• Mice, Transgenic
• MicroRNAs (metabolism)
• Organ Culture Techniques
• Signal Transduction (genetics)
• Stem Cells (physiology)
• Ureter (abnormalities, embryology, pathology)
• Urogenital Abnormalities (genetics, pathology)
• Vesico-Ureteral Reflux (genetics, pathology)