The fate of spermatogonial stem cells in the cryptorchid testes of RXFP2 deficient mice

PLoS One. 2013 Oct 3;8(10):e77351. doi: 10.1371/journal.pone.0077351. eCollection 2013.

Abstract

The environmental niche of the spermatogonial stem cell pool is critical to ensure the continued generation of the germ cell population. To study the consequences of an aberrant testicular environment in cryptorchidism we used a mouse model with a deletion of Rxfp2 gene resulting in a high intra-abdominal testicular position. Mutant males were infertile with the gross morphology of the cryptorchid testis progressively deteriorating with age. Few spermatogonia were identifiable in 12 month old cryptorchid testes. Gene expression analysis showed no difference between mutant and control testes at postnatal day 10. In three month old males a decrease in expression of spermatogonial stem cell (SSC) markers Id4, Nanos2, and Ret was shown. The direct counting of ID4+ cells supported a significant decrease of SSCs. In contrast, the expression of Plzf, a marker for undifferentiated and differentiating spermatogonia was not reduced, and the number of PLZF+ cells in the cryptorchid testis was higher in three month old testes, but equal to control in six month old mutants. The PLZF+ cells did not show a higher rate of apoptosis in cryptorchid testis. The expression of the Sertoli cell FGF2 gene required for SSC maintenance was significantly reduced in mutant testis. Based on these findings we propose that the deregulation of somatic and germ cell genes in the cryptorchid testis, directs the SSCs towards the differentiation pathway. This leads to a depletion of the SSC pool and an increase in the number of PLZF+ spermatogonial cells, which too, eventually decreases with the exhaustion of the stem cell pool. Such a dynamic suggests that an early correction of cryptorchidism is critical for the retention of the SSC pool.

MeSH terms

  • Age Factors
  • Animals
  • Apoptosis
  • Cell Differentiation
  • Cryptorchidism / genetics
  • Cryptorchidism / metabolism
  • Cryptorchidism / pathology*
  • Disease Models, Animal
  • Fibroblast Growth Factor 2 / genetics
  • Fibroblast Growth Factor 2 / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental*
  • Humans
  • Inhibitor of Differentiation Proteins / genetics
  • Inhibitor of Differentiation Proteins / metabolism
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Promyelocytic Leukemia Zinc Finger Protein
  • Proto-Oncogene Proteins c-ret / genetics
  • Proto-Oncogene Proteins c-ret / metabolism
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Receptors, G-Protein-Coupled / deficiency
  • Receptors, G-Protein-Coupled / genetics*
  • Sertoli Cells / metabolism
  • Sertoli Cells / pathology
  • Spermatogonia / growth & development
  • Spermatogonia / metabolism
  • Spermatogonia / pathology*
  • Stem Cells / metabolism
  • Stem Cells / pathology*
  • Testis / growth & development
  • Testis / metabolism
  • Testis / pathology*

Substances

  • Idb4 protein, mouse
  • Inhibitor of Differentiation Proteins
  • Kruppel-Like Transcription Factors
  • Nanos2 protein, mouse
  • Promyelocytic Leukemia Zinc Finger Protein
  • RNA-Binding Proteins
  • RXFP2 protein, mouse
  • Receptors, G-Protein-Coupled
  • Zbtb16 protein, mouse
  • Fibroblast Growth Factor 2
  • Proto-Oncogene Proteins c-ret
  • Ret protein, mouse

Grants and funding

These authors have no support or funding to report.