Six5 is required for spermatogenic cell survival and spermiogenesis

Abstract

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.

The reproductive outcome of female patients with myotonic dystrophy type 1 (DM1) undergoing PGD is not affected by the size of the expanded CTG repeat tract

“…DMPK has a role in diverse cellular functions, ranging from modulation of contractionrelaxation cycle and ion handling to cytoskeletal movement and organelle localization in various muscle tissue types, where DMPK is primarily expressed [28,29]. However little evidence exists on expression patterns in the human hypothalamus, pituitary gland and gonads.…”

Control of KIT signalling in male germ cells: what can we learn from other systems?

“…KIT protein levels are decreased in Six5 K/K mice relative to wild-type mice leading to the suggestion that this reduction in KIT could underlie the disturbed spermatogenic viability and enhanced Leydig cell proliferation (Sarkar et al 2004), although no direct link between SIX5 and KIT gene has been established.…”

Mutagenesis-generated mouse models of human infertility with abnormal sperm

“…Within the regions defined by the swm2, repro2 and repro3 mutations, there are no genes now known to affect sperm morphology and quality; however, the candidate region of swm2 does include a gene whose mutation causes male infertility for reasons other than oligoasthenoteratozoospermia. Mutation of the Six5 gene within the swm2 region causes azoospermia and testicular atrophy (Sarkar et al, 2004). Together, these considerations suggest that ENU mutations affecting sperm morphology are present throughout the genome and not necessarily clustered as found in a study of ENU-induced mutations affecting sperm tail development (Clark et al, 2004).…”

“…[Among all of the genes in the three genomic regions, only one, Six5 (sine oculis-related homeobox 5 homolog), in the swm2 region and encoding a transcription factor, has been implicated in spermiogenesis. The phenotypes of the null mutation in Six5 include lenticular cataracts (Sarkar et al, 2000) as well as an absence of mature spermatozoa, tubular atrophy and concomitant reduction of the testis weight (Sarkar et al, 2004). Although these phenotypes are markedly different than the swm2 phenotype, it is possible that the ENU point mutation swm2 could be within the Six5 locus, as frequently null and hypomorphic phenotypes can differ.…”