Luis F. Parada

My laboratory studies the signaling pathways that control vertebrate neural development and that go awry in tumorigenesis. One focus has been the Trk family of transmembrane RTK receptors for the neurotrophin ligands. Using knockout mutations in mice for the genes encoding the neurotrophins: BDNF, NT3, and NT4/5, as well as the TrkA and TrkB receptors, we studied the essential nature of the neurotrophins and their receptors in the survival of early neurons and more complex phenotypes in the central and peripheral nervous systems. Conditional knockout technology allowed for more precise analysis of neurotrophin function in the CNS, demonstrating a role in development, synaptic plasticity and behavior. These models also proved useful for studying neuropsychiatric disorders, including depression, and we are currently investigating the role of hippocampal neurogenesis in antidepressant response. We have also developed mouse models of human disease including malignant brain tumors, autism, and Neurofibromatosis type 1 (NF-1). We generated Nf1 null mice and conditional knockouts that model the malignancy of NF-1, and are presently studying dermal and plexiform neurofibroma development, Schwann cell development, and learning disabilities. Additionally, mice with mutations in Nf1, p53, and Pten develop brain tumors that resemble human glioma with 100% penetrance. We found 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 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.