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. 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 hope to overcome the reduced life span of the current mouse models that precludes the analysis of neurotrophin function in adulthood and, consequently, the dissection of the full range of NT-3 effects in vivo.

National Institute of Health (NIH)
Division of Basic Sciences - NCI (NCI)
Intramural Research (Z01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Basic Sciences
United States
Zip Code
Takeda, Haruna; Koso, Hideto; Tessarollo, Lino et al. (2013) Musashi1-CreER(T2) : a new cre line for conditional mutagenesis in neural stem cells. Genesis 51:128-34
Rivera, Juan; Tessarollo, Lino (2008) Genetic background and the dilemma of translating mouse studies to humans. Immunity 28:1-4
Taylor, Gregory A; Rodriguiz, Ramona M; Greene, Robert I et al. (2008) Behavioral characterization of P311 knockout mice. Genes Brain Behav :
Nosheny, Rachel L; Ahmed, Farid; Yakovlev, Alexander et al. (2007) Brain-derived neurotrophic factor prevents the nigrostriatal degeneration induced by human immunodeficiency virus-1 glycoprotein 120 in vivo. Eur J Neurosci 25:2275-84
Garcia-Fresco, German P; Sousa, Aurea D; Pillai, Anilkumar M et al. (2006) Disruption of axo-glial junctions causes cytoskeletal disorganization and degeneration of Purkinje neuron axons. Proc Natl Acad Sci U S A 103:5137-42
Dorsey, Susan G; Renn, Cynthia L; Carim-Todd, Laura et al. (2006) In vivo restoration of physiological levels of truncated TrkB.T1 receptor rescues neuronal cell death in a trisomic mouse model. Neuron 51:21-8
Esteban, Pedro F; Yoon, Hye-Young; Becker, Jodi et al. (2006) A kinase-deficient TrkC receptor isoform activates Arf6-Rac1 signaling through the scaffold protein tamalin. J Cell Biol 173:291-9
Fritzsch, Bernd; Tessarollo, Lino; Coppola, Enzo et al. (2004) Neurotrophins in the ear: their roles in sensory neuron survival and fiber guidance. Prog Brain Res 146:265-78
Sedy, J; Szeder, V; Walro, J M et al. (2004) Pacinian corpuscle development involves multiple Trk signaling pathways. Dev Dyn 231:551-63
Szapacs, Matthew E; Mathews, Tiffany A; Tessarollo, Lino et al. (2004) Exploring the relationship between serotonin and brain-derived neurotrophic factor: analysis of BDNF protein and extraneuronal 5-HT in mice with reduced serotonin transporter or BDNF expression. J Neurosci Methods 140:81-92

Showing the most recent 10 out of 14 publications