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

Cancer Requires Support From Immune System to Develop

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, we initially 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 proto-oncogenes that exhibit interesting patterns of expression, in the late eighties we began to pursue functional studies to elucidate essential roles in regulation of embryonic development and, in turn, investigate their roles in cancer using mouse models.

A central effort has focused on the functions of the Trk gene family, which encodes transmembrane receptor tyrosine kinases (RTKs) that act as functional 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 reveal the essential nature of the neurotrophin ligands and their receptors in the survival of early neurons in addition to more complex 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. These mouse models have also proved useful for studying aspects of neuropsychiatric disorders, including depression, and we are currently investigating the role of hippocampal neurogenesis in anti-depressant response. These studies have also been extended to the study of signaling molecules downstream of Trk receptors and with this approach, novel models of autism have been developed and are under study.

Another line of study concerns the modeling of human disease including autism, brain cancer, and Von Recklinghausen's Neurofibromatosis type 1 (NF-1), which is caused by mutation of a tumor suppressor. Our studies of the NF-1 gene have led to the discovery that its protein product, neurofibromin, is a negative regulator of signaling mediated by the Trk receptor tyrosine kinase (RTK). We have generated Nf1 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 Nf1, we are presently studying its role in dermal and plexiform neurofibroma development, Schwann cell development, and learning disabilities. Additionally, mice with mutations in Nf1, p53, and Pten develop brain tumors with 100% penetrance that molecularly and histologically resemble human glioma. Using genetic and stereotactic injection methods, we have shown that these tumors arise from neural stem/progenitor cells that reside within the subventricular zone, a neurogenic niche of the brain. These physiologically relevant mouse models of human glioma and NF1 are powerful tools for investigating the initiation and progression of tumors associated with these devastating diseases and provide a useful biological system for testing possible therapies.  

Selected Publications:

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):920-922.

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 post-synaptic connections of hippocampal schaffer collaterals." Journal of Neuroscience. Vol. 25(15): 3774-3786.

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): 377-388.

Le, L. and Parada, L.F. 2007. “Tumor microenvironment and neurofibromatosis type I: connecting the GAPs.”  Oncogene.  Vol. 26(32): 4609-4616.

Li, Y., Luikart, B.W., Birnbaum, S., Chen, J., Kwon, C.H., Kernie, S.G., Bassel-Duby, R. and Parada, L.F. 2008. “Trk B regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment.”  Neuron. Vol. 59(3): 399-412.

Kwon, C.H., Zhao, D., Chen, J., Alcantara, S., Li, Y., Burns, D., Mason, R., Lee, E. Y-H., Wu, H. and Parada, L.F. 2008. “Pten haploinsufficiency accelerates formation of high grade astrocytomas.”  Cancer Research.  Vol.  68(9):  3286-3294.

Yang, F.C., Ingram, D.A., Chen, S., Zhu, Y., Yuan, J., Li, X., Yang, X, Knowles, S., Horn, W., Li, Y., Zhang, S., Yang, Y., Vakili, S., Yu, M., Burns, D., Robertson, K., Hutchins, G., Parada, L.F.*, and Clapp, D.W. 2008. “NF1-dependent tumors require a microenvironment containing Nf1 /- and c-kit dependent bone marrow.” Cell. Vol. 135(3): 437-448.  (* co-corresponding author)

Alcantara Llaguno, S., Chen, J., Kwon, C.H., Jackson, E.L., Li, Y., Burns, D.K., Alvarez-Buylla, A., and Parada, L.F. 2009. “Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model”.  Cancer Cell. Vol. 15(1): 45-56.

Zhou, J., Blundell, J., Ogawa, S., Kwon, C.H., Zhang, W., Sinton, C., Powell, C.M., and Parada, L.F.  2009. “Pharmacological inhibition of mTORC1 suppresses anatomical, cellular and behavioral abnormalities in neural-specific Pten knock-out mice.”  Journal of Neuroscience. Vol. 29(6): 1773-1783.

Le, L., Shipman, T., Burns, D., and Parada, L.F. 2009. “Cell of origin and microenvironment contribution for NF1-associated dermal neurofibromas.” Cell Stem Cell. Vol. 4(5): 454-463.

To access any of the publications referenced on this website please visit http://www.ncbi.nlm.nih.gov/PubMed