LINE-1 Mediated Insertion into Poc1a (Protein of Centriole 1 A) Causes Growth Insufficiency and Male Infertility in Mice

PLoS Genet. 2015 Oct 23;11(10):e1005569. doi: 10.1371/journal.pgen.1005569. eCollection 2015 Oct.

Abstract

Skeletal dysplasias are a common, genetically heterogeneous cause of short stature that can result from disruptions in many cellular processes. We report the identification of the lesion responsible for skeletal dysplasia and male infertility in the spontaneous, recessive mouse mutant chagun. We determined that Poc1a, encoding protein of the centriole 1a, is disrupted by the insertion of a processed Cenpw cDNA, which is flanked by target site duplications, suggestive of a LINE-1 retrotransposon-mediated event. Mutant fibroblasts have impaired cilia formation and multipolar spindles. Male infertility is caused by defective spermatogenesis early in meiosis and progressive germ cell loss. Spermatogonial stem cell transplantation studies revealed that Poc1a is essential for normal function of both Sertoli cells and germ cells. The proliferative zone of the growth plate is small and disorganized because chondrocytes fail to re-align after cell division and undergo increased apoptosis. Poc1a and several other genes associated with centrosome function can affect the skeleton and lead to skeletal dysplasias and primordial dwarfisms. This mouse mutant reveals how centrosome dysfunction contributes to defects in skeletal growth and male infertility.

Publication types

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

MeSH terms

  • Animals
  • Cell Cycle Proteins
  • Centrioles / genetics
  • Centrosome / metabolism
  • Chromosomal Proteins, Non-Histone / genetics
  • Cytoskeletal Proteins / genetics*
  • Dwarfism / genetics*
  • Dwarfism / pathology
  • Humans
  • Infertility, Male / genetics*
  • Infertility, Male / pathology
  • Long Interspersed Nucleotide Elements / genetics*
  • Male
  • Meiosis / genetics
  • Mice
  • Proteins / genetics
  • Proteins / metabolism
  • Sertoli Cells / metabolism
  • Spermatogenesis / genetics*
  • Spermatogonia / metabolism

Substances

  • CENPW protein, human
  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • Cytoskeletal Proteins
  • POC1A protein, human
  • Poc1a protein, mouse
  • Proteins