Six5 is required for spermatogenic cell survival and spermiogenesis.
Myotonic dystrophy 1 (DM1) is a multi-system disorder characterized by endocrine defects that include testicular and tubular atrophy, oligospermia, Leydig cell hyperproliferation and increased follicle stimulating hormone (FSH) levels. DM1 results from a CTG expansion that causes transcriptional silencing of the flanking SIX5 allele. Loss of Six5 results in male sterility and a progressive decrease in testicular mass with age. We demonstrate a strict requirement of Six5 for both spermatogenic cell survival and spermiogenesis. Leydig cell hyperproliferation and increased intra-testicular testosterone levels are observed in the Six5-/- mice. Although increased FSH levels are observed in the Six5+/- and Six5-/- mice, serum testosterone levels and intra-testicular inhibin alpha and inhibin beta B levels are not altered in the Six5 mutant animals when compared with controls. Significantly, steady-state c-Kit levels are reduced in the Six5-/- testis. Thus, decreased c-Kit levels could contribute to the elevated spermatogenic cell apoptosis and Leydig cell hyperproliferation in the Six5-/- mice. The results support the hypothesis that the reduced SIX5 levels contribute to the male reproductive defects in DM1.
Sarkar
Partha S
PS
Institute for Genetic Medicine, University of Southern California, Keck School of Medicine, Los Angeles 90033, USA.
Paul
Sharan
S
Han
Jennifer
J
Reddy
Sita
S
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D028322:Inhibin-beta Subunits / Q000378:metabolism; D007265:Inhibins / Q000378:metabolism; D007985:Leydig Cells / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009223:Myotonic Dystrophy / Q000235:genetics; D009845:Oligospermia / Q000235:genetics / Q000473:pathology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D013091:Spermatogenesis / Q000502:physiology*; D013737:Testis / Q000378:metabolism* / Q000473:pathology; D013739:Testosterone / Q000378:metabolism
D018398:Homeodomain Proteins; C422402:INHBB protein, human; C486344:Six5 protein, mouse; C094377:inhibin-alpha subunit; D013739:Testosterone; D007265:Inhibins; D028322:Inhibin-beta Subunits; D019009:Proto-Oncogene Proteins c-kit