Alk3 controls nephron number and androgen production via lineage-specific effects in intermediate mesoderm

Development. 2011 Jul;138(13):2717-27. doi: 10.1242/dev.059030. Epub 2011 May 25.

Abstract

The mammalian kidney and male reproductive system are both derived from the intermediate mesoderm. The spatial and temporal expression of bone morphogenetic protein (BMP) 2 and BMP4 and their cognate receptor, activin like kinase 3 (ALK3), suggests a functional role for BMP-ALK3 signaling during formation of intermediate mesoderm-derivative organs. Here, we define cell autonomous functions for Alk3 in the kidney and male gonad in mice with CRE-mediated Alk3 inactivation targeted to intermediate mesoderm progenitors (Alk3(IMP null)). Alk3-deficient mice exhibit simple renal hypoplasia characterized by decreases in both kidney size and nephron number but normal tissue architecture. These defects are preceded by a decreased contribution of Alk3-deleted cells to the metanephric blastema and reduced expression of Osr1 and SIX2, which mark nephron progenitor cells. Mutant mice are also characterized by defects in intermediate mesoderm-derived genital tissues with fewer mesonephric tubules and testicular Leydig cells, epithelial vacuolization in the postnatal corpus epididymis, and decreased serum testosterone levels and reduced fertility. Analysis of ALK3-dependent signaling effectors revealed lineage-specific reduction of phospho-p38 MAPK in metanephric mesenchyme and phospho-SMAD1/5/8 in the testis. Together, these results demonstrate a requirement for Alk3 in distinct progenitor cell populations derived from the intermediate mesoderm.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgens / metabolism*
  • Animals
  • Apoptosis / genetics
  • Apoptosis / physiology
  • Bone Morphogenetic Protein Receptors, Type I / genetics
  • Bone Morphogenetic Protein Receptors, Type I / metabolism*
  • Cell Proliferation
  • Fluorescent Antibody Technique
  • Immunoblotting
  • Immunohistochemistry
  • In Situ Hybridization
  • Kidney / cytology
  • Kidney / embryology
  • Kidney / metabolism
  • Male
  • Mesoderm / embryology
  • Mesoderm / metabolism*
  • Mice
  • Mice, Mutant Strains
  • Models, Biological
  • Nephrons / cytology*
  • Nephrons / metabolism*
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • beta-Galactosidase / genetics
  • beta-Galactosidase / metabolism

Substances

  • Androgens
  • Bmpr1a protein, mouse
  • Bone Morphogenetic Protein Receptors, Type I
  • beta-Galactosidase