Open AccessTfap2a is a novel gatekeeper of nephron differentiation during kidney development
Author(s) -
Brooke E. Chambers,
Gary F. Gerlach,
Eleanor G. Clark,
Karen H. Chen,
Anna E. Levesque,
Ignaty Leshchiner,
Wolfram Goessling,
Rebecca A. Wingert
Publication year - 2019
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.172387
Subject(s) - biology , pronephros , zebrafish , ciliogenesis , kidney development , transcription factor , homeobox , nephron , genetic screen , emx2 , microbiology and biotechnology , genetics , danio , cellular differentiation , gene , embryonic stem cell , kidney , phenotype
Renal functional units known as nephrons undergo patterning events during development that create a segmental array of cellular compartments with discrete physiological identities. Here, from a forward genetic screen using zebrafish we report the discovery that transcription factor AP-2 alpha (tfap2a) coordinates a gene regulatory network that activates the terminal differentiation program of distal segments in the pronephros. We found that tfap2a acts downstream of Iroquois homeobox 3b (irx3b), a distal lineage transcription factor, to operate a circuit consisting of tfap2b, irx1a, and genes encoding solute transporters that dictate the specialized metabolic functions of distal nephron segments. Interestingly, this regulatory node is distinct from other checkpoints of differentiation like polarity establishment and ciliogenesis. Thus, our studies reveal insights into the genetic control of differentiation, where tfap2a is essential to regulate a suite of segment transporter traits at the final tier of zebrafish pronephros ontogeny. These findings have relevance for understanding renal birth defects, as well as efforts to recapitulate nephrogenesis in vivo to facilitate drug discovery and regenerative therapies.