Abstract
BackgroundUp to now, two loci have been involved in XX sex-reversal in mammals following loss-of-function mutations, PIS (Polled Intersex Syndrome) in goats and R-spondin1 (RSPO1) in humans. Here, we analyze the possible interaction between these two factors during goat gonad development. Furthermore, since functional redundancy between different R-spondins may influence gonad development, we also studied the expression patterns of RSPO2, 3 and 4.ResultsSimilarly to the mouse, RSPO1 shows a sex-dimorphic expression pattern during goat gonad development with higher levels in the ovaries. Interestingly, the PIS mutation does not seem to influence its level of expression. Moreover, using an RSPO1 specific antibody, the RSPO1 protein was localized in the cortical area of early differentiating ovaries (36 and 40 dpc). This cortical area contains the majority of germ cell that are surrounded by FOXL2 negative somatic cells. At latter stages (50 and 60 dpc) RSPO1 protein remains specifically localized on the germ cell membranes. Interestingly, a time-specific relocation of RSPO1 on the germ cell membrane was noticed, moving from a uniform distribution at 40 dpc to a punctuated staining before and during meiosis (50 and 60 dpc respectively). Interestingly, also RSPO2 and RSPO4 show a sex-dimorphic expression pattern with higher levels in the ovaries. Although RSPO4 was found to be faintly and belatedly expressed, the expression of RSPO2 increases at the crucial 36 dpc stage, as does that of FOXL2. Importantly, RSPO2 expression appears dramatically decreased in XX PIS-/- gonads at all three tested stages (36, 40 and 50 dpc).ConclusionDuring goat ovarian development, the pattern of expression of RSPO1 is in agreement with its possible anti-testis function but is not influenced by the PIS mutation. Moreover, our data suggest that RSPO1 may be associated with germ cell development and meiosis. Interestingly, another RSPO gene, RSPO2 shows a sex-dimorphic pattern of expression that is dramatically influenced by the PIS mutation.
Highlights
Up to now, two loci have been involved in XX sex-reversal in mammals following loss-of-function mutations, Polled intersex syndrome (PIS) (Polled Intersex Syndrome) in goats and R-spondin1 (RSPO1) in humans
RSPO2 is a candidate gene for ovarian differentiation Interestingly, we found that another R-spondin gene, RSPO2 has a female specific sex-dimorphic expression pattern and that its expression is affected in XX PIS-/gonads
The present study brings evidences that RSPO1 could have a role correlated with germ cell differentiation and maintenance before and during meiosis
Summary
Two loci have been involved in XX sex-reversal in mammals following loss-of-function mutations, PIS (Polled Intersex Syndrome) in goats and R-spondin (RSPO1) in humans. Following SRY expression, in the future supporting cells of the XY bipotential gonad, SOX9 remains up-regulated and Sertoli cell differentiation occurs [5]. The crucial role of SOX9 in testis differentiation has been demonstrated by gain and loss of function mutations in mice [6,7,8,9]. In human and domestic animals, XX male phenotypes can result from homozygous mutations in anti-testis genes expressed in ovaries [13]. Two loci have been proved to be associated with complete XX sex-reversal, PIS in goat [16] and more recently, RSPO1 in human [17]
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