TMEM63B Regulates Nucleocytoplasmic Transport and Placental Development

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.