Genetic analysis of the role of Alx4 in the coordination of lower body and external genitalia formation

Eur J Hum Genet. 2014 Mar;22(3):350-7. doi: 10.1038/ejhg.2013.160. Epub 2013 Aug 14.

Abstract

Although several syndromes include abnormalities of both the ventral body wall and external genitalia, the developmental bases of this correlation are largely unknown. Naturally occurring mutations in Aristaless-like 4 (Alx4, Strong's luxoid: Alx4Lst) have ventral body wall and pelvic girdle abnormalities. We sought to determine whether the development of the genital tubercle (GT) and its derivatives, the external genitalia, is affected by this mutation. We thus performed genetic and tissue labeling analyses in mutant mice. Alx4Lst/Lst mutants displayed hypoplasia of the dorsal GT and reduced expression of Fibronectin. We analyzed cell migration during GT formation by tissue labeling experiments and discovered that the cells located in the proximal segment of the umbilical cord (infra-umbilical mesenchyme) migrate toward the dorsal part of the GT. The Alx4Lst/Lst mutants also displayed augmented expression of Hh signal-related genes. Hence, we analyzed a series of combinatorial mutants for Alx4, Sonic hedgehog (Shh) and GLI-Kruppel family member 3 (Gli3). These phenotype-genotype analyses suggested a genetic interaction between Alx4 and Hh signaling during GT formation. Moreover, Hh gain-of-function mutants phenocopied some of these phenotypes. These observations reveal novel information regarding the pathogenic mechanisms of syndromic lower ventral body malformations, which are largely unknown.

Publication types

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

MeSH terms

  • Animals
  • Cell Movement
  • Female
  • Genitalia / abnormalities*
  • Genitalia / embryology
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism
  • Male
  • Mesenchymal Stem Cells / metabolism
  • Mesenchymal Stem Cells / physiology
  • Mice
  • Mutation*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Pelvis / abnormalities*
  • Pelvis / embryology
  • Umbilical Cord / embryology
  • Umbilical Cord / pathology
  • Zinc Finger Protein Gli3

Substances

  • Alx4 protein, mouse
  • Gli3 protein, mouse
  • Hedgehog Proteins
  • Homeodomain Proteins
  • Kruppel-Like Transcription Factors
  • Nerve Tissue Proteins
  • Shh protein, mouse
  • Zinc Finger Protein Gli3