Neurogenesis plays a critical role in brain physiology and behavioral performance, and defective neurogenesis leads to neurological and psychiatric disorders. Here, we show that PLCβ4 expression is markedly reduced in SENP2-deficient cells and mice, resulting in decreased IP formation and altered intracellular calcium homeostasis. PLCβ4 stability is regulated by the SUMO-dependent ubiquitin-mediated proteolytic pathway, which is catalyzed by PIAS2α and RNF4. SUMOylated PLCβ4 is transported to the nucleus through Nup205- and RanBP2-dependent pathways and regulates nuclear signaling. Furthermore, dysregulated calcium homeostasis induced defects in neurogenesis and neuronal viability in SENP2-deficient mice. Finally, SENP2 and PLCβ4 are stimulated by starvation and oxidative stress, which maintain calcium homeostasis regulated neurogenesis. Our findings provide mechanistic insight into the critical roles of SENP2 in the regulation of PLCβ4 SUMOylation, and the involvement of SENP2-PLCβ4 axis in calcium homeostasis regulated neurogenesis under stress.