Development of the urogenital system is regulated via the 3′UTR of GDNF

Autor:	Anmol Kumar, Satu Kuure, Hannu Sariola, Yujuan Gui, Petra Sipilä, Jaan-Olle Andressoo, Hao Li, Roxana Ola, Madis Jakobson
Přispěvatelé:	Helsinki Institute of Life Science HiLIFE, Joint Activities, Kidney development, Institute of Biotechnology, Helsinki Institute of Life Science HiLIFE, Faculty of Medicine, Department of Biochemistry and Developmental Biology, University of Helsinki, Medicum, Hannu Sariola / Principal Investigator, Koe-eläinkeskus / Muuntogeeniyksikkö, HUS Abdominal Center, Helsinki One Health (HOH)
Jazyk:	angličtina
Rok vydání:	2019
Předmět:	Male 0301 basic medicine animal diseases Kidney development lcsh:Medicine Apoptosis Kidney Mice 0302 clinical medicine Cell Movement Neurotrophic factors Glial cell line-derived neurotrophic factor lcsh:Science 3' Untranslated Regions Multidisciplinary Stem Cells Cell Cycle Gene Expression Regulation Developmental ASSOCIATION FAMILY Cell biology medicine.anatomical_structure Ureteric bud Female Signal Transduction RENAL AGENESIS Mice Transgenic Biology Article CELL-PROLIFERATION 03 medical and health sciences Organ Culture Techniques medicine KIDNEY DEVELOPMENT Animals Humans Glial Cell Line-Derived Neurotrophic Factor Progenitor cell Progenitor Vesico-Ureteral Reflux VITAMIN-A Three prime untranslated region urogenital system lcsh:R Embryo Mammalian Disease Models Animal MicroRNAs 030104 developmental biology nervous system Infertility Urogenital Abnormalities BRANCHING MORPHOGENESIS biology.protein 1182 Biochemistry cell and molecular biology lcsh:Q 3111 Biomedicine Ureter NEPHRIC DUCT INSERTION RET 030217 neurology & neurosurgery NEUROTROPHIC FACTOR
Zdroj:	Scientific Reports, Vol 9, Iss 1, Pp 1-14 (2019) Scientific Reports
ISSN:	2045-2322
DOI:	10.1038/s41598-019-40457-1
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3add9908784710903c7b78c7e3b1c7f2 http://link.springer.com/article/10.1038/s41598-019-40457-1 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
Nepřihlášeným uživatelům se plný text nezobrazuje	K zobrazení výsledku je třeba se přihlásit.