The role of neurotrophin-dependent gene expression in the developing somatosensory nervous system

The precise matching of an innumerable number of neurons with coordinate targets is a task of unimaginable magnitude that must be accomplished by the mammalian nervous system during development. Nowhere better is this principle exemplified than in the somatosensory nervous system, where developing neurons of the embryonic dorsal root ganglion (DRG) depend on trophic signals from growth factors secreted by target organs for the proper establishment of their connections. These molecules, collectively known as neurotrophic factors have been extensively studied, yet the intracellular mechanisms by which neurotrophic factors function in DRG neurons are incompletely understood.;In this dissertation, I explore the mechanism by which the prototypic neurotrophin nerve growth factor (NGF) regulates the development of DRG neurons. NGF is expressed in the skin, to which a subset of DRG neurons extend axons. The association of target derived NGF with its receptor TrkA at growing axonal termini leads to the activation of signaling pathways that are retrogradely transported to the cell body, and ultimately, to the nucleus. Here, activation of nuclear transcription factors by NGF-derived signals leads to the expression of target genes, many of which are directly responsible for mediating the functions of NGF in somatosensory nervous system development. Thus, signaling from NGF to downstream gene expression programs can be broadly divided into a two-step process: (1) Activation of transcription factors by NGF (2) Expression of NGF target genes.;In the first part of my dissertation, I discuss my attempt to characterize the function of the stimulus-dependent transcription factor, Serum Response Factor (SRF). SRF is expressed in DRG neurons, and its activity is stimulated by NGF signaling. Upon analysis of SRF function, a striking resemblance both in vitro and in vivo between DRG neurons lacking SRF and those deprived of NGF is observed; in both cases, these neurons show dramatic defects in the extension and arborization of peripheral axonal projections in the target field in vivo, and defects in axonal outgrowth in vitro. These findings suggest that SRF is a mediator of NGF dependent target innervation by sensory neurons.;In the second part of my dissertation, I explore how SRF and other NGF dependent transcription factors influence further development of DRG neurons by controlling the expression of NGF target genes. To this end, I describe the function of an NGF target gene---the tyrosine kinase Ret. Ret is embryonically expressed in a class of NGF-responsive DRG neurons, known as nonpeptidergic neurons. NGF-dependent expression of Ret, in turn controls expression of a subset NGF-dependent target genes in nonpeptidergic neurons, and is important for the acquisition of normal neuronal size and innervation of the epidermis by nonpeptidergic sensory axons. Overall, these findings suggest that NGF exerts its influence on target innervation at two hierarchical levels, both through the direct activation of transcription factors such as SRF, and indirectly, through the expression of downstream target genes such as Ret, which in turn, controls further innervation by a subset of NGF-dependent neurons. Collectively, my work studying both the mechanisms of NGF signaling and the functions of NGF target genes provide a framework in which to understand how neurotrophins orchestrate the development and maintenance of the peripheral nervous system.