Pax 2/8-regulated Gata 3 expression is necessary for morphogenesis and guidance of the nephric duct in the developing kidney.
The mammalian pro- and mesonephros are transient embryonic kidneys essential for urogenital system development. The nephric (Wolffian) duct, which is a central constituent of both structures, elongates caudally along a stereotypical path to reach the hindlimb level where it induces metanephros (adult kidney) formation, while the remaining duct gives rise to the male genital tract (epidydimis, vas deferens). The transcription factors Pax2 and Pax8 are essential for the initiation of pro- and mesonephros development. In a cDNA microarray screen for genes specifically expressed in the pro/mesonephros and regulated by Pax proteins, we identified Gata3, a transcription factor gene associated with hypoparathyroidism, deafness and renal anomaly (HDR) syndrome. Gata3 is already expressed in the pronephric anlage, together with Pax2 and Pax8, suggesting that it may be a direct Pax2/8 target gene. Inactivation of Gata3 by insertion of an Ires-GFP reporter gene resulted in a massive increase in nephric duct cellularity, which was accompanied by enhanced cell proliferation and aberrant elongation of the nephric duct. Interestingly, however, the nephrogenic cord extended, with delayed kinetics, along the entire caudal path up to the level of the hindlimb bud, indicating that extension of the nephric duct and cord is controlled by different guidance cues. At the molecular level, the nephric duct of Gata3(-/-) embryos is characterized by the loss of Ret expression and signaling, which may contribute to the guidance defect of the nephric duct. Together, these results define Gata3 as a key regulator of nephric duct morphogenesis and guidance in the pro/mesonephric kidney.
Grote
David
D
McGill Cancer Centre and Biochemistry Department, McGill University, 3655 Promenade Sir-William-Osler, Montreal, Quebec H3G 1Y6, Canada.
Souabni
Abdallah
A
Busslinger
Meinrad
M
Bouchard
Maxime
M
D000818:Animals; D017931:DNA Primers; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D020868:Gene Silencing; D049452:Green Fluorescent Proteins; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D007668:Kidney / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D051762:PAX2 Transcription Factor / Q000378:metabolism; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism; D014928:Wolffian Ducts / Q000196:embryology* / Q000378:metabolism
D017931:DNA Primers; D050990:GATA3 Transcription Factor; D051762:PAX2 Transcription Factor; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; C497319:Pax2 protein, mouse; C499496:Pax8 protein, mouse; D049452:Green Fluorescent Proteins