Pax2 and pax8 regulate branching morphogenesis and nephron differentiation in the developing kidney.
Pax genes are important regulators of kidney development. In the mouse, homozygous Pax2 inactivation results in renal agenesis, a phenotype that has largely precluded the analysis of Pax gene function during metanephric kidney development. To address this later function, kidney development was analyzed in embryos that were compound heterozygous for Pax2 and for Pax8, a closely related member of the Pax gene family. Both genes are coexpressed in differentiating nephrons and collecting ducts. At the morphological level, Pax2(+/-)Pax8(+/-) metanephric kidneys are severely hypodysplastic and characterized by a reduction in ureter tips and nephron number in comparison with wild-type or Pax2(+/-) kidneys. In developing nephrons, the molecular analysis of Pax2(+/-)Pax8(+/-) kidneys reveals a strong reduction in the expression levels of Lim1, a key regulator of nephron differentiation, accompanied by an increase in apoptosis. At a more mature stage, the reduction of Pax2/8 gene dosage severely affects distal tubule formation, revealing a role for Pax genes in the differentiation of specific nephron segments. At the ureter tips, the expression of Wnt11, a target of glial cell-derived neurotrophic factor-Ret signaling, is significantly reduced, whereas the expression levels of Ret and GDNF remain normal. Together, these results demonstrate a crucial role for Pax2 and Pax8 in nephron differentiation and branching morphogenesis of the metanephros.
Narlis
Melina
M
McGill Cancer Centre and Biochemistry Department, McGill University, 3655 Promenade Sir-William-Osler, Montreal, Quebec H3G 1Y6, Canada.
Grote
David
D
Gaitan
Yaned
Y
Boualia
Sami K
SK
Bouchard
Maxime
M
D000818:Animals; D002454:Cell Differentiation; D002470:Cell Survival; D018507:Gene Expression Regulation, Developmental; D007668:Kidney / Q000196:embryology*; D007686:Kidney Tubules, Distal / Q000196:embryology; D051379:Mice; D008809:Mice, Inbred C3H; D009024:Morphogenesis; D009399:Nephrons / Q000196:embryology*; D051762:PAX2 Transcription Factor / Q000235:genetics / Q000502:physiology*; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000502:physiology*; D051153:Wnt Proteins / Q000235:genetics
D051762:PAX2 Transcription Factor; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; C497319:Pax2 protein, mouse; C499496:Pax8 protein, mouse; D051153:Wnt Proteins; C508957:Wnt11 protein, mouse