Open AccessHedgehog-GLI signaling inFoxd1-positive stromal cells promotes nephrogenesis Via TGFβ signaling
Author(s) -
Christopher J. Rowan,
Winny Li,
Hovhannes Martirosyan,
Steven Erwood,
Di Hu,
Yun-Kyo Kim,
Sepideh Sheybani-Deloui,
Jaap Mulder,
Joshua Blake,
Lin Chen,
Norman D. Rosenblum
Publication year - 2018
Publication title -
development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.754
H-Index - 325
eISSN - 1477-9129
pISSN - 0950-1991
DOI - 10.1242/dev.159947
Subject(s) - biology , smoothened , nephron , hedgehog signaling pathway , stromal cell , microbiology and biotechnology , hedgehog , medicine , sonic hedgehog , kidney , gene knockdown , endocrinology , signal transduction , cancer research , cell culture , genetics
Normal kidney function depends on the proper development of the nephron, the functional unit of the kidney. Reciprocal signaling interactions between the stroma and nephron progenitor compartment have been proposed to control nephron development. Here, we show that removal of Hedgehog intracellular effector Smoothened (Smo-deficient mutants) in the cortical stroma results in an abnormal renal capsule, and an expanded nephron progenitor domain with an accompanying decrease in nephron number via a block in epithelialization. We show that stromal-Hedgehog-Smo signaling acts through GLI3 repressor. Whole kidney RNA sequencing and analysis of FACS-isolated stromal cells identified impaired TGFβ2 signaling in Smo-deficient mutants. We show that neutralization and knockdown of TGFβ2 in explants inhibited nephrogenesis. In addition, we demonstrate that concurrent deletion of Tgfbr2 in stromal and nephrogenic cells in vivo results in decreased nephron formation and an expanded nephrogenic precursor domain similar to that observed in Smo-deficient mutant mice. Together, our data suggest a mechanism whereby a stromal Hedgehog-TGFβ2 signaling axis acts to control nephrogenesis.