Neurotrophins are a highly homologous family of secreted growth factors that have been extensively studied for their roles in the proliferation, survival, and differentiation of various cell populations in the mammalian nervous system. The activities of these molecules have led to an increasing interest in their use as therapeutic agents for certain neurodegenerative diseases. More recently, neurotrophins have also been shown to exert a variety of pleiotropic responses on malignant cells, and the expression of their receptors in specific cancers (such as neuroblastomas and medulloblastomas) has been correlated to a specific patient prognosis.? ? Neurotrophin function is mediated by two types of receptors: the unique p75 neurotrophin receptor, a member of the tumor necrosis factor receptor family that binds all neurotrophins with similar affinity, and the tyrosine kinase receptors of the Trk gene family. Trk receptors (in addition to the well-studied full-length tyrosine kinase receptors) include several isoforms, some of which lack the kinase domain. However, there is very little or no information about the developmental functions of specific isoforms of Trk receptors. In vitro studies have provided clues to the mechanism of function of these receptor isoforms, but have proved insufficient in unraveling their role in development. Genetic ablation experiments in mice have confirmed the essential role of neurotrophins and Trk receptors in the development of specific classes of neurons of the peripheral nervous system. Recently, we have shown that they also contribute to the functional phenotype of subpopulations of neurons of the central nervous system, namely of the serotonergic system.? ? One focus of our laboratory is the trkC receptors and their ligand neurotrophin-3 (NT-3). Both the trkC and NT-3 genes have unique features among their gene families. The trkC gene generates several receptors, some of which (e.g., isoforms with an insertion in the catalytic region) are unique among the Trk genes. NT-3 is the only neurotrophin that binds all Trk receptors, although with different affinities. Over the past few years, we have generated in vivo data supporting specific roles for trkC receptors. By gene replacement strategy, we have also provided evidence that, in addition to trkC, NT-3 also activates other Trk receptors during development. We are now dissecting neurotrophin functions in vivo by generating and analyzing murine models in which specific isoforms are deleted by gene-targeting technology. Furthermore, by introducing these targeted deletions with an inducible system, we have overcome the reduced life span of the initially generated mouse models that precluded the analysis of neurotrophin function in adulthood and, consequently, the dissection of the full range of NT-3 effects in vivo.
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