TMBIM family proteins regulate neuronal differentiation through modulation of ER and lysosomal Ca²⁺ homeostasis

TMBIM family proteins (TMBIM1-6), which are involved in Ca²⁺ regulation, potentially modulate intracellular calcium dynamics that are critical for early neuronal developmental processes. However, the functions of most TMBIM family proteins during embryonic development remain poorly defined. Here, we investigated the functions of TMBIM family proteins in embryonic development and show that TMBIM family proteins regulate neuronal development by enhancing SOCE activity and lysosomal Ca 2+ release. Specifically, gene disruption in zebrafish or brain-specific knockdown in Drosophila led to defective neurogenesis, resulting in neurodevelopmental disorders, including autism-like phenotypes. Loss of TMBIM genes downregulated key neuronal developmental genes by suppressing ADNP and NFAT family protein expression, which are regulated by TBR1. In TMBIM-depleted neuronal cells, Ca 2+ refilling SOCE activity or lysosomal Ca 2+ release via TPC channel opening was decreased by inhibiting releasable ER Ca 2+ . This impairment attenuated TBR1 gene expression, thereby suppressing neuronal differentiation. Also, it restricted calcineurin activation and the resultant NFAT nuclear translocation, and its transcriptional activation regulated neuronal differentiation. These observations demonstrated the contribution of TMBIM genes to early embryonic development by regulating ER Ca 2+ -oriented Ca 2+ homeostasis, including SOCE and lysosomal Ca 2+ and its related gene activation.