TMEM63B regulates nucleocytoplasmic transport and placental development.

The placental development requires coordinated trophoblast proliferation and differentiation, processes tightly coupled to cell cycle control. Here, we identify TMEM63B, an osmo/mechano-sensitive ion channel, as a key regulator of trophoblast cell cycle progression and placental development. TMEM63B modulates nucleocytoplasmic transport (NCT) by stabilizing NCT components, which govern the nuclear shuttling of key cell cycle regulators in response to osmo/mechanical cues. Loss of TMEM63B compromises Ran protein expression and Ran-XPO1 complex, impairing the nuclear export of CDKN1A/p21. This disruption leads to defective trophoblast proliferation, placental dysfunction, and ultimately perinatal lethality. Our findings establish TMEM63B as a pivotal osmo/mechano-sensitive molecule that regulates nucleocytoplasmic shuttling, providing new insights into how mechanical cues are integrated into nuclear mechanoresponses and placental development.