A missense mutation in the Capza3 gene and disruption of F-actin organization in spermatids of repro32 infertile male mice

Dev Biol. 2009 Jun 1;330(1):142-52. doi: 10.1016/j.ydbio.2009.03.020. Epub 2009 Mar 31.

Abstract

Males homozygous for the repro32 ENU-induced mutation produced by the Reproductive Genomics program at The Jackson Laboratory are infertile, have low epididymal sperm concentrations, and produce sperm with abnormally shaped heads and poor motility. The purpose of the present study was to identify the mutated gene in repro32 mice and to define the structural and functional changes causing infertility and the aberrant sperm phenotype. In repro32/repro32 mice, we discovered a failure to shed excess cytoplasm and disorganization of the middle piece of the flagellum at spermiation, resulting in the outer dense fibers being wrapped around the sperm head within a bag of cytoplasm. Using a candidate-gene approach, a mutation was identified in the spermatid-specific "capping protein (actin filament) muscle Z-line, alpha 3" gene (Capza3). CAPZA3 protein localization was altered in spermatids concurrent with altered localization of a unique CAPZB variant isoform and disruption of the filamentous actin (F-actin) network. These observations strongly suggest the missense mutation in Capza3 is responsible for the mutant phenotype of repro32/repro32 sperm and regulation of F-actin dynamics by a spermatogenic cell-specific CAPZ heterodimer is essential for removal of the cytoplasm and maintenance of midpiece integrity during spermiation in the mouse.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actins / metabolism
  • Actins / ultrastructure*
  • Amino Acid Sequence
  • Animals
  • CapZ Actin Capping Protein / analysis
  • CapZ Actin Capping Protein / genetics*
  • CapZ Actin Capping Protein / metabolism
  • Fluorescent Antibody Technique
  • Infertility, Male / genetics*
  • Infertility, Male / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Mice, Transgenic
  • Microscopy, Electron, Transmission
  • Molecular Sequence Data
  • Mutation, Missense*
  • Phenotype
  • Sperm Motility
  • Spermatids / metabolism
  • Spermatids / ultrastructure*

Substances

  • Actins
  • CAPZA3 protein, mouse
  • CapZ Actin Capping Protein