Genetic control mechanisms of long-term neuronal survival

PROJECT SUMMARY The proposed research aims to unravel fundamental mechanisms behind neuronal survival across an organism's lifespan, shedding light on specialized RNA regulation pivotal for prolonged neuronal resilience. Essential for learning, memory, and environmental adaptation, mature neurons must persist throughout an organism's life, yet our understanding of the intricate genetic regulations enabling this endurance remains incomplete. Prior studies predominantly emphasized competition for external cues and growth factors in establishing neural circuits and preventing cell death. Our research uncovers intrinsic genetic mechanisms facilitating continuous neuronal survival. Notably, during differentiation, neurons alter their apoptosis regulation, becoming more resistant to cell death triggers. This transformation coincides with global reprogramming of apoptosis-related genes at both transcriptional and post-transcriptional levels, resulting in the generation of neural-specific alternative isoforms. A significant focus lies on understanding the role of specific gene elements which exhibit crucial regulatory functions. We have determined a dozen of these splicing controls with implicated functions in controlling neuronal survival and cell death. Our preliminary data show that splicing alternation significantly impairs neuronal health. We propose three independent and interrelated overarching aims for systematic exploration of these elements in influencing neuronal apoptosis. Additionally, by investigating the impact of exon deletions and genetic manipulations, we seek to determine their continuous necessity for long-term neuronal survival. Our interdisciplinary team, adept in genetics, neurobiology, molecular cellular biochemistry, and computational biology, uniquely positions us to tackle these critical questions. Through innovative methodologies and rigorous investigations, we endeavor to unveil neuron- specific regulatory mechanisms governing apoptosis competence. Such discoveries may not only reshape our comprehension of intrinsic neuronal survival strategies but also pave the way for novel strategies to enhance neuronal resilience and combat neurological disorders affecting brain tissue equilibrium and circuitry formation.