Dkk1 in the peri-cloaca mesenchyme regulates formation of anorectal and genitourinary tracts.

Abstract

Anorectal malformation (ARM) is a common birth defect but the developmental history and the underlying molecular mechanism are poorly understood. Using murine genetic models, we report here that a signaling molecule Dickkopf-1 (Dkk1) is a critical regulator. The anorectal and genitourinary tracts are major derivatives of caudal hindgut, or the cloaca.Dkk1 is highly expressed in the dorsal peri-cloacal mesenchymal (dPCM) progenitors. We show that the deletion of Dkk1 causes the imperforate anus with rectourinary fistula. Mutant genital tubercles exhibit a preputial hypospadias phenotype and premature urethral canalization.Dkk1 mutants have an ectopic expansion of the dPCM tissue, which correlates with an aberrant increase of cell proliferation and survival. This ectopic tissue is detectable before the earliest sign of the anus formation, suggesting that it is most likely the primary or early cause of the defect. Deletion of Dkk1 results in an elevation of the Wnt/ß-catenin activity. Signaling molecules Shh, Fgf8 and Bmp4 are also upregulated. Furthermore, genetic hyperactivation of Wnt/ß-catenin signal pathway in the cloacal mesenchyme partially recapitulates Dkk1 mutant phenotypes. Together, these findings underscore the importance ofDKK1 in regulating behavior of dPCM progenitors, and suggest that formation of anus and urethral depends on Dkk1-mediated dynamic inhibition of the canonical Wnt/ß-catenin signal pathway.

• Authors: Chaoshe Guo, Ye Sun, Chunming Guo, Bryan T MacDonald, Joseph G Borer, Xue Li
• Journal: Developmental biology (Dev Biol) Vol. 385 Issue 1 Pg. 41-51 (Jan 01 2014) ISSN: 1095-564X [Electronic] United States
• PMID: 24479159 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2013 Published by Elsevier Inc.

Chemical References

• Bmp4 protein, mouse
• Bone Morphogenetic Protein 4
• Dkk1 protein, mouse
• Fgf8 protein, mouse
• Hedgehog Proteins
• Intercellular Signaling Peptides and Proteins
• Shh protein, mouse
• Wnt Proteins
• beta Catenin
• Fibroblast Growth Factor 8

Topics

• Anal Canal (abnormalities, embryology)
• Animals
• Anorectal Malformations
• Anus, Imperforate (embryology, genetics)
• Bone Morphogenetic Protein 4 (biosynthesis)
• Cell Differentiation (genetics)
• Cell Proliferation
• Cell Survival (genetics)
• Enzyme Activation (genetics)
• Fibroblast Growth Factor 8 (biosynthesis)
• Hedgehog Proteins (biosynthesis)
• Intercellular Signaling Peptides and Proteins (genetics, metabolism)
• Male
• Mesoderm (embryology, metabolism)
• Mice
• Mice, Transgenic
• Rectum (abnormalities, embryology)
• Stem Cells
• Up-Regulation
• Urogenital Abnormalities (embryology, genetics)
• Urogenital System (embryology)
• Wnt Proteins (metabolism)
• Wnt Signaling Pathway
• beta Catenin (metabolism)