The Role of Store-Operated Calcium Entry in Transcription Factor Activation and in Accelerated Differentiation of Induced Pluripotent Stem Cell-Neural Progenitor Cells Derived from Bipolar Disorder Patients

Hewitt, Tristen
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University of Guelph

Calcium (Ca2+) is a pivotal signaling molecule in non-excitable and excitable cells. In neurons, it regulates processes from transcription to excitability. Though they have specialized Ca2+ channels that influx massive amounts of this cation during activity, these channels are closed during rest. So, to regulate smaller oscillations, neurons use store-operated Ca2+ entry (SOCE). This mechanism utilizes the ER Ca2+ sensor STIM and the Ca2+ channel ORAI for influx after Ca2+ stores in the ER are depleted. This influx is known to regulate transcription, differentiation, survivability, and excitability, among other processes. Since the various roles SOCE contributes to are cell type-specific, we wanted to assess its impact on transcription and differentiation with a model seldom used for SOCE-specific research: human-derived neural progenitor cells (NPCs). SOCE is known to modulate activity of transcription factors such as NFAT and Sp4. We sought to test whether CREB, a crucial transcription factor in neurogenesis, could be modulated by SOCE. We found that CREB was phosphorylated as soon as five minutes after SOCE activation, though not by one of its canonical pathways. We also found that SOCE activation contributed broadly to transcription as its activation upregulated several immediate early genes. If SOCE indeed influences neurogenesis in this way, dysregulation in the brain could contribute to neurodevelopmental disease. Though Ca2+ signaling is known to be dysregulated in bipolar disorder (BD), few studies have explored potential SOCE dysregulation in cells derived from these patients. We uncovered an attenuation in SOCE-specific Ca2+ influx in BD-derived NPCs (BD-NPCs) that was dependent on differentiation. From this we explored neurodevelopmental deficits in these cells, which included a unique transcriptome, upregulated microRNAs, reduced rate of proliferation, increased migration, longer neurite outgrowth, and abnormal subventricular structures after generating BD organoids. This all suggests that BD pathophysiology may begin long before symptoms of the disease present in early adulthood. Continuing to study the impact SOCE has on NPCs and how dysregulated neurodevelopmental processes in BD-NPCs contribute to disease could uncover new cell signaling pathways and potential therapeutics for the disease.

calcium, store-operated calcium entry, neurodevelopment, bipolar disorder, induced pluripotent stem cells, neural progenitor cells, differentiation