Professor of Biochemistry & Biophysics, UNC-CH
PHD - University of Texas, Houston
HONORS & AWARDS
Axon Guidance and Signal Transduction in Nervous System Development
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.
- Buhusi M, Schlatter MC, Demyanenko GP, Thresher R, Maness PF. L1 interaction with ankyrin regulates mediolateral topography in the retinocollicular projection. J Neurosci. 2008 Jan 2;28(1):177-88
- Wright AG, Demyanenko GP, Powell A, Schachner M, Enriquez-Barreto L, Tran TS, Polleux F, Maness PF. Close homolog of L1 and neuropilin 1 mediate guidance of thalamocortical axons at the ventral telencephalon. J Neurosci. 2007 Dec 12;27(50):13667-79
- Schlatter MC, Buhusi M, Wright AG, Maness PF. CHL1 promotes Sema3A-induced growth cone collapse and neurite elaboration through a motif required for recruitment of ERM proteins to the plasma membrane. J Neurochem. 2008 Feb;104(3):731-44. Epub 2007
- Maness PF, Schachner M. Neural recognition molecules of the immunoglobulin superfamily: signaling transducers of axon guidance and neuronal migration.
- Nat Neurosci. 2007 Jan;10(1):19-26. Review. Erratum in: Nat Neurosci. 2007 Feb;10(2):263
- Sullivan PF, Keefe RS, Lange LA, Lange EM, Stroup TS, Lieberman J, Maness PF. NCAM1 and neurocognition in schizophrenia. Biol Psychiatry. 2007 Apr 1;61(7):902-10. Epub 2006
- Hinkle CL, Diestel S, Lieberman J, Maness PF. Metalloprotease-induced ectodomain shedding of neural cell adhesion molecule (NCAM). J Neurobiol. 2006 Oct;66(12):1378-95
3020 Genetic Medicine Bldg
Campus Box 7260
Chapel Hill, NC 27599