Department of Developmental Biology and Cancer Research, Institute of Medical Research Israel-Canada, The Hebrew University- Faculty of Medicine, Jerusalem, Israel.
Medical Genetics Institute, Shaare Zedek Medical Center, the Hebrew University Hadassah Medical School, Jerusalem, Israel.
Elife. 2022 Mar 21;11:e72632. doi: 10.7554/eLife.72632.
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 or specific knockdown of Nup107 in the gonadal soma resulted in ovarian-dysgenesis-like phenotypes. Transcriptomic analysis identified the somatic sex-determination gene ) 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 loss. Importantly, the aberrant phenotypes induced by compromising either or are reminiscent of bone morphogenetic protein (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.
我们最近在 Nucleoporin107（Nup107；D447N）中发现了一个错义突变，该突变是导致 XX 卵巢发育不全的原因，这是一种罕见的疾病，其特征是卵巢发育不良和功能障碍。在 中对人类突变进行建模或特异性敲低 Nup107 在性腺体中导致卵巢发育不全样表型。转录组分析确定了体性性别决定基因 作为 Nup107 的靶标。将 Dsx 确立为 Nup107 的主要相关靶标，无论是在性腺体中丢失还是获得 Dsx，都足以模拟或挽救由 缺失引起的表型。重要的是，通过削弱 或 而引起的异常表型类似于骨形态发生蛋白（BMP）信号超激活。值得注意的是，在这种情况下，金属蛋白酶 AdamTS-A 是 Dsx 和 Nup107 的转录靶标，对于 BMP 信号的校准是必要的。由于 BMP 信号的调节是体细胞-生殖细胞相互作用的一个保守关键决定因素，Nup107 对 Dsx-F 的性别和组织特异性部署似乎对于维持生殖细胞和体性腺细胞之间的体内平衡至关重要。
