Abstract
NR5A1 is essential for the development and for the function of steroid producing glands of the reproductive system. Moreover, its misregulation is associated with endometriosis, which is the first cause of infertility in women. Hr39, the Drosophila ortholog of NR5A1, is expressed and required in the secretory cells of the spermatheca, the female exocrine gland that ensures fertility by secreting substances that attract and capacitate the spermatozoids. We here identify a direct regulator of Hr39 in the spermatheca: the Gcm transcription factor. Furthermore, lack of Gcm prevents the production of the secretory cells and leads to female sterility in Drosophila. Hr39 regulation by Gcm seems conserved in mammals and involves the modification of the DNA methylation profile of mNr5a1. This study identifies a new molecular pathway in female reproductive system development and suggests a role for hGCM in the progression of reproductive tract diseases in humans.
Highlights
Gcm murine orthologs, which were described for their expression in placenta, parathyroid, thymus, kidney and nervous system[25,26,27,28,29], are expressed in the uterus
Drosophila, the complete lack of the Gcm protein leads to embryonic lethality due to the transformation of glial cells into neurons[24,30,31]
Allow the analysis of gcm mutant animals at later stage[24,31,32,33]: the gcmrA87 allele is due to the insertion of a P-element containing the LacZ gene in the promoter of gcm and the gcmGal[4] allele has been produced upon replacement of the LacZ by the Gal[4] gene[24,31,32,33]
Summary
Gcm murine orthologs (mGCM1 and mGCM2), which were described for their expression in placenta, parathyroid, thymus, kidney and nervous system[25,26,27,28,29], are expressed in the uterus. Assays in cells indicate that the Gcm family promotes the expression of mNR5A1/hNR5A1 and that the mGCM proteins induce the same changes in the DNA methylation of the hNR5a1 locus as those observed in endometriosis. Our data reveal the regulatory pathway underlying SC differentiation in the Drosophila spermatheca and the conserved regulation of Hr39 and NR5A1, which represents the first evidence of the functional conservation of the Gcm transcription factors. Understanding the regulation of Hr39 expression may shed light on the physiopathological mechanisms of the major cause of infertility in women
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