Six1 and Eya1 are critical regulators of peri-cloacal mesenchymal progenitors during genitourinary tract development

Dev Biol. 2011 Dec 1;360(1):186-94. doi: 10.1016/j.ydbio.2011.09.020. Epub 2011 Sep 24.


The evolutionarily conserved Six1-Eya1 transcription complex is central to mammalian organogenesis, and deletion of these genes in mice results in developmental anomalies of multiple organs that recapitulate human branchio-oto-renal (BOR) and DiGeorge syndromes. Here, we report that both Six1 and Eya1 are strongly expressed in the peri-cloacal mesenchyme (PCM) surrounding the cloaca, the terminal end of hindgut dilation. Six1 and Eya1 are absent from the intra-cloacal mesenchyme (ICM), a cell mass that divides the cloaca into dorsal hindgut and ventral urogenital sinus. Deletion of either or both Six1 and Eya1 genes results in a spectrum of genitourinary tract defects including persistent cloaca - hypoplastic perineum tissue between external urogenital and anorectal tracts; hypospadias - ectopic ventral positioning of the urethral orifice; and hypoplastic genitalia. Analyses of critical signaling molecules indicate normal expression of Shh in the cloaca and cloaca-derived endodermal epithelia. Using a Cre/loxP genetic fate mapping strategy, we demonstrate that Six1-positive PCM progenitors give rise to the most caudal structures of the body plan including the urogenital and anorectal complex, and the perineum region. Thus, Six1 and Eya1 are key regulators of both upper and lower urinary tract morphogenesis. Results from this study uncover essential roles of the PCM progenitors during genitourinary tract formation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Patterning
  • Bone Morphogenetic Proteins / genetics
  • Bone Morphogenetic Proteins / metabolism
  • Cell Proliferation
  • Cell Survival
  • Cloaca / embryology*
  • Cloaca / metabolism*
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / metabolism
  • Female
  • Gene Expression Regulation, Developmental
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Humans
  • Intracellular Signaling Peptides and Proteins / deficiency
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Mesoderm / cytology
  • Mesoderm / embryology
  • Mesoderm / metabolism
  • Mice
  • Mice, Knockout
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Models, Biological
  • Nuclear Proteins / deficiency
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Pregnancy
  • Protein Tyrosine Phosphatases / deficiency
  • Protein Tyrosine Phosphatases / genetics
  • Protein Tyrosine Phosphatases / metabolism*
  • Signal Transduction
  • Urogenital Abnormalities / embryology
  • Urogenital Abnormalities / genetics
  • Urogenital Abnormalities / metabolism
  • Urogenital System / embryology*
  • Urogenital System / metabolism*


  • Bone Morphogenetic Proteins
  • Homeodomain Proteins
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • Six1 protein, mouse
  • Eya1 protein, mouse
  • Protein Tyrosine Phosphatases