Affiliations: 1) IMRIC, The Hebrew University- Faculty of Medicine; 2) Weizmann Institute of Science, Rehovot, Israel; 3) The Hadassah Hebrew University Medical Center, Jerusalem, Israel; 4) Division of Pediatric Endocrinology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.; 5) Princeton University, Princeton, NJ, USA
Keywords: d. gonads; l. gonads
We previously identified a missense mutation in the nucleoporin-107 (Nup107; D447N) as the cause for XX-ovarian-dysgenesis in five female cousins from a consanguineous family. All men in the family had normal pubertal development and those married have multiple children. Nup107 is an essential component of the nuclear pore complex expressed ubiquitously in a sex-non-specific manner. Modelling of the human mutation in Drosophila or specific knockdown of Nup107 in the gonadal soma resulted in ovarian-dysgenesis-like phenotypes, while male flies were fully fertile. To uncover the targets of Nup107 that mediate its sex and tissue specific activity, we conducted a genome-wide transcriptomic analysis on larval gonads compromised for Nup107. We identified 82 candidate genes which displayed significant changes in mRNA expression, including doublesex (dsx), the somatic sex-determination gene. Either loss or gain of Dsx in the gonadal soma is sufficient to mimic or rescue the phenotypes induced by Nup107 loss, establishing Dsx as a primary relevant target of Nup107. Importantly, the aberrant phenotypes induced by compromising either Nup107 or dsx are reminiscent of BMP signaling hyperactivation. Remarkably, in this context, the metalloprotease AdamTS-A, a transcriptional target of both Dsx and Nup107, is necessary for the calibration of BMP signaling. We also uncovered the cellular impairments underlying BMP signaling dysregulation. As modulation of BMP signaling is a conserved critical determinant of soma-germline interaction, the sex and tissue specific deployment of Dsx-F by Nup107 seems crucial for the maintenance of the homeostatic balance between the germ cells and somatic gonadal cells.