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Implications of Pgrmc1 Regulation of Kit Ligand Synthesis in the Hippocampus

The mammalian hippocampus is responsible for many crucial brain functions such as learning, memory, and neurogenesis in adults. Its degeneration is a pathology associated with the early stages of Alzheimer’s disease. A variety of genes have been associated with both neuroprotection and neurogenesis in the brain, some of which include progesterone membrane component 1 (Pgrmc1) and kit ligand (KitL). Pgrmc1 is recognized for mediating hormonal functions in both the ovary and neuroendocrine regions such as the anteroventral periventricular nucleus (AVPV), but its functions in the hippocampus are not well known. Both Pgrmc1 and KitL share downstream targets, the most strongly supported being genes in the Janus kinase (Jak)/signal transducer and activator of transcription (Stat) pathway. I hypothesized that Pgrmc1 regulates neural targets through KitL/c-Kit signaling. To investigate this hypothesis I used a variety of in vivo and in vitro techniques. These techniques included mapping both KitL and receptor c-Kit in the adult female rat brain using in situ hybridization. I used Pgrmc1 silencing with siRNA in hippocampal-derived mHe-18 cells and Pgrmc1/2 double conditional knock out mouse brains to study Pgrmc1 regulation of KitL synthesis. To determine common downstream targets of KitL and Pgrmc1 I then treated mHe-18 cells with soluble KitL protein. Finally, to determine whether c-Kit mediated effects of Pgrmc1, I treated cells with both Pgrmc1 siRNA and AG-1296, a c-Kit inhibitor. The results show that Pgrmc1 regulates KitL expression, as well as downstream targets Pias1, 2, 3, and 4. However, AG-1296 did not abrogate Pgrmc1 regulation of the downstream targets, demonstrating regulation independent of KitL signaling. Taken together, these results suggest that while Pgrmc1 alters KitL expression and regulates the same genes as KitL/c-Kit, the mechanism of action likely differs. Considering that these two genes are involved in neurogenesis and neuroprotection, as well as memory and learning, a better understanding of the pathways may help lead the way in treating neurodegenerative diseases in the future.
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