Nucleoporin107 mediates female sexual differentiation via Dsx

Abstract

We recently identified a missense mutation in Nucleoporin107 (Nup107; D447N) underlying XX-ovarian-dysgenesis, a rare disorder characterized by underdeveloped and dysfunctional ovaries. Modeling of the human mutation in Drosophila or specific knockdown of Nup107 in the gonadal soma resulted in ovarian-dysgenesis-like phenotypes. Transcriptomic analysis identified the somatic sex-determination gene doublesex (dsx) as a target of Nup107. Establishing Dsx as a primary relevant target of Nup107, either loss or gain of Dsx in the gonadal soma is sufficient to mimic or rescue the phenotypes induced by Nup107 loss. 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. 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.

From the sideline: Tissue‐specific nucleoporin function in health and disease, an update

“…Homozygous mutations in NUP107 (Table 2) have been identified underlying ovarian dysgenesis (MIM 618078; [108]) and premature ovarian insufficiency [109,110]. Disease modelling in mice and Drosophila as well as specific knock-down of Nup107 in Drosophila gonadal soma led to ovarian dysgenesis-like phenotypes [109,111]. Transcriptome analysis identified the sex-determination gene doublesex (dsx) as primary target downstream of Nup107 in Drosophila.…”

“…Over-expression of Dsx on the other hand rescued the phenotypes induced by Nup107 loss. Moreover, the authors identified the secreted metalloprotease AdamTS-A as an important downstream target of both Nup107 and Dsx [111]. AdamTS-A is necessary for the calibration of BMP signalling and modulation of BMP signalling critical for soma-germline interaction [111].…”

“…Moreover, the authors identified the secreted metalloprotease AdamTS‐A as an important downstream target of both Nup107 and Dsx [111]. AdamTS‐A is necessary for the calibration of BMP signalling and modulation of BMP signalling critical for soma‐germline interaction [111]. Together these data suggest that NUP107 regulates the conserved BMP‐Dsx axis, which appears to be critical for maintaining the homeostatic balance between germ cells and somatic gonadal cells and thus for proper gonad development [111].…”

Evolutionary, structural and functional insights in nuclear organisation and nucleocytoplasmic transport in trypanosomes

“…These diseases can also arise through alterations in the NPC composition, in subunit levels (sequestration, aggregation or overexpression) or in nucleocytoplasmic transport [ 72 ]. Such alterations lead to a range of pathologies, including neurodegenerative diseases (e.g., dementia, Huntington's, Alzheimer, Parkinson's) [ 125 ], autoimmune disorders (Systemic lupus erythematosis, rheumatic disease), cancer [ 126 ], renal [ 127 , 128 ] and ovary dysfunction [ 129 , 130 ].…”