| The proper wiring of the nervous system is a task of marvelous complexity and intricacy that in mammals demands the specific point-to-point connections of many millions of neurons. Precision in neuron-to-target connectivity is thought to be achieved during development by the overproduction of individual neurons and the selective maintenance of only those that are correctly routed. Mechanistically, this is best understood in the peripheral nervous system and is explained by the neurotrophic hypothesis, which states that developing neurons growing towards their targets must compete for limited amounts of pro-survival factors produced by their targets. These survival and growth-promoting molecules, collectively known as neurotrophic factors, are strictly required for the establishment and maintenance of the peripheral nervous system, yet the intracellular mechanisms by which they function in individual neurons remain poorly understood. We have investigated the extent to which neurotrophin-induced nuclear activation and gene expression are necessary for orchestrating such profound cellular phenotypic effects as growth and survival. We observed a striking resemblance in vivo between peripheral neurons lacking the general transcription factor CREB and those deprived of neurotrophic factors; in both cases, neurons exhibited axonal growth defects and ultimately died by apoptosis. We concluded that CREB functions as a key effector of neurotrophin function in vivo, and thus sought next to delineate the mechanisms by which neurotrophins exert specific control over CREB-dependent gene expression. We have found, in contrast to what is widely-held, that CREB binding to its response elements (CREs) within target gene promoters is not constitutive, but is stimulus-inducible and correlates with gene transcription. Further, we believe that this inducible DNA binding activity is regulated by a novel, redox-dependent signaling pathway. Finally, we have undertaken an extensive screen for neurotrophin-regulated genes in vivo, to identify the genomic tools upon which these cells depend to carry out neurotrophin-imparted instructions. These lines of work, investigating both the mechanisms of neurotrophin signaling to the nucleus and the gene targets of neurotrophin activation, should together provide a platform from which to understand how these crucial factors function in the establishment and maintenance of the nervous system. |
