TMEM63B Regulates Nucleocytoplasmic Transport and Placental Development

The placenta is critical for embryonic development, orchestrating nutrient exchange, hormone production, and immune protection. Trophoblast proliferation and differentiation, governed by precise cell cycle regulation, are fundamental to placental development. Here, we identify TMEM63B, an osmo/mechano-sensitive ion channel, as a key regulator of trophoblast cell cycle progression and placental development. Our findings show that TMEM63B modulates nucleocytoplasmic transport (NCT), particularly through its impact on the Ran-XPO1-RanGAP1 complex, which governs the nuclear shuttling of key cell cycle regulators in response to mechanical cues. Loss of TMEM63B results in a reduction of Ran protein levels, destabilizing the export machinery and impairing the nuclear export of CDKN1A (p21), a critical cell cycle inhibitor. This disruption leads to defective trophoblast proliferation, placental dysfunction, and ultimately embryonic lethality. Our findings establish TMEM63B as a pivotal mechanosensitive molecule that regulates nucleocytoplasmic shuttling, providing new insights into how mechanical cues are integrated into nuclear mechanoresponses and placental development.