
Luis F. Parada, Ph.D.
Ph.D., Massachusetts Institute of Technology - 1985
Chairman, Department of Developmental Biology
Diana and Richard C. Strauss Distinguished Chair in Developmental Biology
Director, Kent Waldrep Center for Basic Research on Nerve Growth and Regeneration
Southwestern Ball Distinguished Chair in Basic Neuroscience Research
American Cancer Society Research Professor
Genetics and Development
Neuroscience
Office: (214) 648-1822
FAX: (214) 648-1960
Building NB, Room 5.208
E-mail: Luis.Parada@UTSouthwestern.edu
Our long-standing interest lies in the elucidation of intracellular regulatory pathways that control the complex process of vertebrate development. To this end, early on we studied the developmental expression of various proto-oncogenes in a search for clues that might give insight into regulatory developmental pathways. Through the discovery of protooncogenes that exhibit interesting patterns of expression, we have pursued functional studies to demonstrate essential roles in regulation of aspects of embryonic development and in turn to identify their roles in mouse models of human cancer.
A central effort has 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. In the past we have made gene targeted knockout mutations in mice by homologous recombination 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 and TrkB receptors. These studies have allowed us to identify the essential nature of the neurotrophin ligands and their receptors in the survival of early neurons in addition to unexpected phenotypes in the central and peripheral nervous systems. More recent application of conditional knockout technology makes it possible to mutate the Trk family and neurotrophin family genes in specific tissues or cell types. This approach allows more precise analysis of neurotrophin function in the CNS where evidence points to a role in development, synaptic plasticity and behavior. We hope these mouse models will provide platforms to study aspects of neuropsychiatric disorders. In addition, we have studied the transcriptional regulation of Trk receptors. We consider this approach a fruitful one as it should provide information about the molecules that regulate target genes essential for normal development of the nervous system.
Another line of study concerns the modeling of the human disease, Von Recklinghausen's Neurofibromatosis type 1 (NF-1), which is caused by mutation of a tumor suppressor. Our studies of the NF-1 gene has led to the discovery that its protein product, termed neurofibromin, is a negative regulator of signaling mediated by the Trk receptor tyrosine kinase (RTK). We have generated NF-1 null mice that have become an important model for the NF-1 disease as it relates to malignancy. Through more recent generation of conditional knockouts of NF-1 we are presently studying its role in brain tumors, Schwann cell development, and learning disabilities.
Efforts to integrate our understanding of neurotrophin function and the NF-1 tumor suppressor activity are further being employed to explore ways of inducing nerve cell survival and regeneration in CNS and spinal cord injury models.
Selected References:
Kaplan, D. R., Martin-Zanca, D., and Parada, L.F . 1991. Tyrosine phosphorylation and tyrosine kinase activity of the trk proto-oncogene product induced by NGF. Nature. Vol. 350(6320): 158-160.
Kaplan, D.R., Hempstead, B.L., Martin-Zanca, D., Chao, M.V., and Parada, L.F . 1991. The trk proto-oncogene product: A signal transducing receptor for Nerve Growth Factor. Science. Vol. 252: 554-558.
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 . 1991. The neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 are ligands for the trkB tyrosine kinase receptor. Cell.Vol. 65: 895-903.
Vogel, K.S., Brannan, C.I., Jenkins, N.A., Copeland, N.G., and Parada, L.F . 1995. Loss of neurofibromin results in neurotrophin-independent survival of embryonic sensory and sympathetic neurons. Cell. Vol. 82: 733-742.
Vogel, K.S., Klesse, L.J., Velasco-Miguel, S., Meyers, K., Rushing, E.J., and Parada, L.F . 1999. Mouse tumor model for neurofibromatosis Type 1. Science. Vol. 286: 2176-2179.
Zhu, Y., Romero, M., Ghosh, P., Charnay, P., Rushing, E.J., Marth, J. and Parada, L.F . 2001. Ablation of NF1 function in neurons induces abnormal development of cerebral cortex and reactive gliosis in the CNS and PNS. Genes & Development. Vol. 15: 859-876.
Zhu, Y., Ghosh, P., Charnay, P., Burns, D.K., and Parada, L.F. 2002. Neurofibromas in NF1:Schwann cell origin and role of tumor environment. Science. Vol. 296(5569):920-2.
Ma, L., Harada, T., Harada, C., Romero, M., Hebert, J.M., McConnell, S.K., and Parada, L.F. 2002. Neurotrophin-3 is required for appropriate establishment of thalamocortical connections. Neuron. Vol 36, 623-634.
Benson, M.B., Romero, M.I., Lush, M.E., Lu, Q.R., Henkemeyer, M., and Parada, L.F. 2005. "Ephrin-B3 is a Myelin-Based Inhibitor of Neurite Outgrowth". Proc. Natl. Acad. Sci., U.S.A. Vol. 102(30): 10694—10699.
Luikart, B.W., Nef, S., Virmani, T., Liu, Y., Kavalali, E.T., and Parada, L.F. 2005. "TrkB has a Cell Autonomous Role in Establishment of Pre- and Postsynaptic Connections of Hippocampal Schaffer Collaterals" Journal of Neuroscience. Vol. 25(15): 3774-3786.
Lei, L. , Laub, F., Lush, M., Romero, M. , Zhou, J., Liker, B., Klesse, L., Ramirez, F., and Parada, L.F. 2005. "The zinc finger transcription factor Klf7 is required for TrkA gene expression and development of nociceptive sensory neurons." Genes & Development. Vol. 19(11):1354-64.
Zhu, Y., Guignard, F., Zhao, D., Burns, D.K., Mason, R.P., and Parada, L.F. 2005. "Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma." Cancer Cell. Vol. 8(2): 119-130.
Zhu, Y., Harada, T., Lush, M.E., Guignard, F., Liu, L., Harada, C., Burns, D.K., Bajenaru, M.L., Gutmann, D.H., Messing, A., and Parada, L.F. 2005. "Inactivation of NF1 in CNS causes increased proliferation in glial progenitor cells and is sufficient to induce optic gliomas." Development. Vol. 132(24): 5577-5588.
Kwon, C.H., Luikart, B.W., Powell, C.M., Zhou, J., Matheny, S.A., Zhang, W., Li, Y., Baker, S.J. and Parada, L.F. 2006. "Pten Regulates Neuronal Arborization and Social Interaction in Mice." Neuron. Vol. 50(3):377-88.
To access any of the publications referenced on this website please visit http://www.ncbi.nlm.nih.gov/PubMed