Our long-standing interest lies in the elucidation of regulatory pathways that control the complex process of nervous system development and the consequences of inappropriate development which can include behavioral and mood disorders as well as cancer. We have focused on the functions of the trk gene family, which encodes transmembrane receptor tyrosine kinases (RTKs) that act as receptors for the nerve growth factor (NGF) family of neurotrophin ligands. Through the use of knockouts and conditional knockouts for the genes encoding the neurotrophins: brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), neurotrophin 4/5 (NT4/5), as well as for the TrkA, TrkB and TrkC receptors we study deficiencies in the formation of the nervous system. In addition to roles in sensory and sympathetic neuron survival, we have identified roles for the neurotrophins in CNS in stem cell development, nerve sprouting and synapse formation. Loss of function in discrete CNS regions can lead to complex behavioral disorders some of which may model neuropsychiatric disorders.
A related line of study of the human disease Von Recklinghausen’s Neurofibromatosis (NF1) which is a classic familial cancer disease. Study of the NF1 tumor suppressor have yielded unexpected findings in the regulation of neurotrophin signaling within the cell. We have developed mouse models of NF1 that replicate the tumor phenotypes in human including tumors of the peripheral nervous system and glioblastoma.
A third area of research focuses on identifying molecules in myelin that inhibit nerve regeneration after injury. We have developed evidence the ephrins, molecules with nerve outgrowth inhibitory properties during embryonic development, have potent myelkin based inhibitory function in the mature spinal cord.
RESEARCH INTERESTS
Developmental Neurobiology
Neurotrophins
Mouse Medels of CNS Tumors
Neurofibromatosis
Spinal Cord Injury
RECENT PUBLICATIONS
Gitler, A.D.*, Zhu, Y.*, Lu, M.M., Parada, L.F., and Epstein, J.A., "The Type 1 Neurofibromatosis (Nf1) gene product has distinct and essential roles in neural crest and endothelial cells" Nature Genetics, 33:75-79, 2003
Luikart, B.W., Nef, S., Virmani, T., Liu, Y., Kavalali, E.T., and Parada, L.F, "TrkB has a Cell Autonomous Role in Establishment of Pre- and Postsynaptic Connections of Hippocampal Schaffer Collaterals" Journal of Neuroscience, 25(15):3774-3786, 2005
Lei, L., Laub, F., Lush, M., Romero, M. , Zhou, J., Liker, B., Klesse, L., Ramirez, F., and Parada, L.F, "The zinc finger transcription factor Klf7 is required for TrkA gene expression and development of nociceptive sensory neurons" Genes & Development, 19(11):1354-64, 2005
Benson, M.B., Romero, M.I., Lush, M.E., Lu, Q.R., Henkemeyer, M., and Parada, L.F, "Ephrin-B3 is a Myelin-Based Inhibitor of Neurite Outgrowth" Proc. Natl. Acad. Sci., U.S.A., 102(30):10694?10699, 2005
Zhu, Y., Guignard, F., Zhao, D., Burns, D.K., Mason, R.P., and Parada, L.F, "Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma" Cancer Cell, 8(2):119-130, 2005
SIGNIFICANT PUBLICATIONS
Kaplan, D.R., Hempstead, B.L., Martin-Zanca, D., Chao, M.V., and Parada, L.F, "The trk proto-oncogene product: A signal transducing receptor for Nerve Growth Factor" Science, 252:554-558, 1991
Soppet, D., Escandon, E., Maragos, J., Middlemas, D.S., Reid, S.W., Blair, J., Burton, L. E., Stanton, B.R., Kaplan, D.R., Hunter, T., Nikolics, K., and Parada, L.F, "The neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 are ligands for the trkB tyrosine kinase receptor" Cell, 65:895-903, 1991
Vogel, K.S., Brannan, C.I., Jenkins, N.A., Copeland, N.G. and Parada, L.F, "Loss of neurofibromin results in neurotrophin-independent survival of embryonic sensory and sympathetic neurons." Cell, 82:733-742, 1995
Vogel, K.S., Klesse, L.J., Velasco-Miguel, S., Meyers, K., Rushing, E.J. and Parada, L.F, "Mouse tumor model for neurofibromatosis Type 1" Science, 286:2176-2179, 1999
Zhu, Y., Ghosh, P., Charnay, P., Burns, D.K., and Parada, L.F, "Neurofibromas in NF1:Schwann cell origin and role of tumor environment" Science, 3;296(5569):920-922, May 2002
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