Regulatory mechanisms of neuronal differentiation and death by necdin

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Necdin is expressed in terminally differentiated neurons, and enforced expression of this protein suppresses cell growth. Necdin binds to the transcription factors E2F1 and p53, both of which are involved in neuronal apoptosis, and suppresses their activities. Recently necdin is thought to be a candidate gene for Prader-Willi syndrome, a genomic imprinting-associated neurobehavioral syndrome. Therefore, necdin may be a pivotal factor that controls terminal differentiation and apoptosis in neurons. In this study, we analyzed the molecular interactions between necdin and its target proteins to gain insights into molecular background behind neuronal terminal differentiation and apoptosis. The results obtained are : 1) We isolated two cDNAs encoding proteins that interacts with necdin by yeast two-hybrid assay. One is the cytoplasmic calcium binding protein NEFA, and the other is the nuclear matrix protein hnRNP U. 2) NEFA is localized to the cytoplasm and endoplasmic reticulum, and regulates calcium metabolism in cooperation with necdin. 3) Both necdin and hnRNP U are localized to nuclear matrix and form a complex to suppress cell growth. 4) Necdin is abundant in the cytosol in differentiated neurons. 5) Necdin binds to specific G-rich motif and functions as a transcription repressor. These results suggest that necdin is involved in neuronal terminal differentiation and survival by interacting with various protein present in neuronal nucleus and cytoplasm.