Our laboratory focuses on the mechanisms of growth and differentiation of neuronal and glial cells. Receptor and non-receptor tyrosine kinases transduce extracellular signals from cell adhesion molecules (CAMs), as well as growth and differentiation factors into intracellular events leading to changes in gene expression and the cytoskeleton. L1, NCAM, integrins, and cadherins are important adhesion molecules that regulate the growth of neuronal processes during development and synaptogenesis. Mouse gene knockouts implicate these adhesion molecules in axonal and dendritic growth during development and in learning and memory in the adult. To define the roles of these CAMs in development and plasticity, we are identifying the intracellular signaling cascades induced by binding interactions of L1 and NCAM. We have found that L1 and NCAM stimulate the mitogen-activated kinase (MAPK) pathway and activate cAMP regulatory element binding protein (CREB), a transcription factor crucial for long term memory. Regulation of these signaling pathways is under investigation in the laboratory.
Mutations in the human L1 gene leads to an X-linked mental retardation syndrome termed CRASH (corpus callosum agenesis,
retardation, aphasia, spasticity, and hydrocephalus). We are analyzing the effects of L1 mutations on signal transduction,
axon guidance, and cytoskeletal interactions, and are characterizing L1 knockout mice as a model for the disease. L1 minus
mice display many interesting features of the CRASH syndrome including defects in neuronal process extension, hippocampal
development, and hydrocephalus. These mice are being exploited to elucidate the normal function of L1 and reveal how L1
mutations lead to the phenotype of the CRASH syndrome.
Genetic screens are used to identify novel protein tyrosine kinases and phosphatases important in neural growth and differentiation. We identified a new receptor tyrosine kinase, termed Rek, which bears extracellular immunoglobulin and fibronectin III domains. We have established a novel assay applicable to any orphan receptor, using the yeast expression vector Pichia pastoris to identify the Rek ligand. The Rek ligand is expected to regulate glial growth and differentiation in the retina. Uncontrolled neural growth in the eye occurs upon retinal detachment, diabetes, and ocular tumors, leading to blindness.
We are fortunate to be a part of the UNC Neuroscience Center and Neurobiology Curriculum for Graduate Research. Association with the Neuroscience Center enables us to participate in the Developmental Neuroscience Mini-Series (a bi-weekly presentation forum), a weekly neuroscience seminar series, and the annual symposium. Students from the Neurobiology Curriculum are welcome to rotate in the lab.
As a Principal Investigator of the NIMH-funded UNC Silvio Conte Center for Schizophrenia Research, I participate in weekly journal clubs and laboratory research discussions on joint projects in clinical and basic neuroscience aspects of schizophrenia.
Our lab is also affiliated with the UNC Neurological Disease Research Center (NDRC) which offers symposia, graduate training, and opportunities for collaboration in such areas as autism, fragile X syndrome, and cognition.
We are fortunate to have many outstanding investigators both here at UNC and elsewhere in the neuroscience community with whom we collaborate including Drs. Eva Anton (cortical neuron migration), Anthony LaMantia (22q11 genes, neuronal patterning), Franck Polleux (thalamocortical axon guidance), Patrick Sullivan (neurogenetics), William Snider (neurotrophins, axon guidance), and Dr. Melitta Schachner (University of Hamburg, and Keck Center, NJ).