A Signal Transduction Pathway that Promotes Neuronal Survival
During the development of the nervous system there is a critical balance between the survival and death of developing neurons. Neurons that form the proper connections received trophic support from their targets and survive whereas neurons that fail to compete effectively for target derived neurotrophic factors die by a process of programmed cell death termed apoptosis. Research over the last decade had defined the molecular underpinnings of the apoptotic process, but the molecular mechanisms by which target derived neurotrophic factors suppress apoptosis and promote survival were unknown. Investigators in this IDDRC have made outstanding contributions to the understanding of the mechanisms by which neurotrophic factors promote survival in the developing nervous system. These include elucidation of the signaling pathways by which neurotrophins regulate gene transcription, and establishing the importance of CREB as a mediator of neurotrophin-dependent neuronal survival (Cell 1994, Science1996). In addition, it was discovered by investigators in our IDDRC that a primary function of the serine/threonine kinase Akt is to mediate cell survival (Science 1997). This seminal finding opened the flood gates for a huge number of studies implicating Akt in the process of cell survival. Following up on this finding, Children’s Hospital IDDRC investigators identified the first Akt substrates, the Bcl2 family member BAD (Cell 1997), and the forkhead transcription factor FOXO3a (Cell 1999; Science 2004), that mediate Akt-dependent survival. A series of elegant studies established the mechanism by which Akt phosphorylation regulates the activity of BAD and FOXO3a to promote cell survival. These studies provided the first mechanistic insight into how growth factors promote cell survival, identified possible mechanisms to explain the etiology of a variety of neurodegenerative disorders, and have suggested possible therapies for treating these neurodenerative disorders. The papers describing these discoveries stand out as landmarks in the field and are among most highly cited papers in biology in the last five years.