1976 BS, Biology, California Institute of Technology, Pasadena, CA
1988 Ph.D., Biology, University of California, San Diego, CA
Postdoctoral Studies, Salk Institute, La Jolla, CA
Email address: carylai(at)indiana.edu
Our laboratory is studying the role of the receptor tyrosine kinases, the "ErbBs" (ErbBs 1-4) and their ligands, the "neuregulins" (NRGs 1-4) in the mature and developing nervous system. NRG1 is best known as a key regulator of Schwann cell function and as a regulator of acetylcholine receptor (AChR) expression in muscle cells in vitro. Our primary focus has been the analysis of mice deficient in the expression of ErbB4 in the nervous system and on the production of transgenic mice that permit the regulated expression of NRG1.
Our studies have revealed that ErbB4 is expressed by multiple populations of tangentially migrating neuronal precursors. During development, ErbB4 marks the migrating interneuronal precursors as they move from the ganglionic eminences to the cortex and hippocampus. In mature mice, ErbB4 is expressed by cells in the rostral migratory stream (RMS), the primary site of neurogenesis in the adult rodent brain. The RMS contains interneuronal precursors that are born in the subventricular zone near the lateral ventricle and that migrate to the olfactory bulb. In both populations of cells, the loss of ErbB4 leads to a reduction in the number of interneurons and to deficits in migration. Our current efforts are directed toward understanding the precise molecular role that ErbB4 plays in these migrating cells.
A preliminary behavioral characterization of ErbB4-deficient mice has revealed a reduction in anxiety-like behavior. As ErbB4 is expressed at high levels in the intercalated cells of the amygdala, we are testing the hypothesis that a loss of ErbB4 function in this region may account for this behavioral alteration.
We are also evaluating neuregulin function by establishing lines of transgenic mice that permit the regulated expression of NRG1. We have developed a system permitting expression in cholinergic neurons, through the use a bacterial artificial chromosome (BAC) encoding choline acetyltransferase. Temporal regulation is provided by the tetracycline system. As NRG1 has been identified as a susceptibility gene for schizophrenia, these mice should help to assess the role of this factor in the diverse mechanisms proposed for the etiology of this disorder including cell migration, neurotransmitter receptor expression and activity, interneuronal function and myelination.
We are also using a BAC-based approach to produce mice permitting regulated expression in dopaminergic neurons and the medium spiny neurons in the striatum. Along with the mice permitting regulated expression in cholinergic neurons, these 3 types of transgenic lines should prove useful for those attempting to produce models of neurodegenerative disorders including Alzheimer's, Parkinson's and Huntington's diseases, which are characterized by functional deficits in cholinergic, dopaminergic and striatal medium spiny neurons, respectively.
Milner, R.J., Lai, C., Lenoir, D., Nave, K.-A., Bakhit, C., and Malfroy, B. (1986). Brain-specific gene expression. Biochem. Soc. Symp., 52, 107-117.
Lai, C. and Lemke, G. (1994). Structure and expression of the Tyro-10 receptor tyrosine kinase. Oncogene, 9, 877-883.
Yau, H.J., Wang, H.F., Lai, C., and Liu, F.-C. (2003) Neural development of the neuregulin receptor ErbB4 in the cerebral cortex and the hippocampus: preferential expression by interneurons tangentially migrating from the ganglionic eminences. Cereb. Cortex, 13, 252-264.
Rimer, M., Prieto, A.L., Weber, J.L., Colasante, C., Ponomareva, O., Fromm, L., Schwab, M.H., Lai, C. and Burden, S.J. (2004) Neuregulin-2 is synthesized by motor neurons and terminal Schwann cells, and activates acetylcholine receptor transcription in muscle cells expressing ErbB4. Mol. Cell. Neurosci., 26, 271-281.
Michailov, G.V., Sereda, M.W., Brinkmann, B.G., Fischer, T.M., Haug, B., Birchmeier, C., Role, L., Lai, C., Schwab, M.H. and Nave, K.-A. (2004) Axonal neuregulin-1 regulates myelin sheath thickness. Science, 304, 700-703.
Flames, N., Long, J.E., Garratt, A.N., Fischer, T.M., Gassmann, M., Birchmeier, C., Lai, C., Rubenstein, J.L.R., and Marin, O. (2004) Short- and long-range attraction of cortical interneurons by Neuregulin-1. Neuron, 44, 252-261.
Anton, E.S., Ghashghaei, H.T., Weber, J.L., McCann, C., Fischer, T.M., Cheung, I.D., Gassmann, M., Messing, A., Klein, R., Schwab, M.H., Lloyd, K.C.K. and Lai, C. (2004) Receptor tyrosine kinase ErbB4 modulates neuroblast migration and placement in the adult forebrain. Nat. Neurosci., 7, 1319-1328.
Garcia-Rivello, H., Taranda, J., Said, M., Cabeza-Meckert, P., Vila-Petroff, M., Scaglione, J., Ghio, S., Chen, J., Lai, C., Laguens, R.P., Lloyd, K.C. and Hertig, C.M. (2005) Dilated cardiomyopathy in ErbB4-deficient ventricular muscle. Am. J. Physiol. Heart Circ Physiol., 289, H1153-1160.
Lai, C. (2005) Peripheral glia: Schwann cells in motion. Curr. Biol., 15, R332-333.
Ponomareva, O., Ma, H., Dakour, R., Raabe, T.D., Lai, C., and Rimer, M. (2005) Stimulation of acetylcholine receptor transcription by Neuregulin-2 requires an N-box response element and is regulated by alternative splicing. Neuroscience, 134, 495-503.
Ghashghaei, H.T., Weber, J.L., Pevny, L., Schmid, R., Schwab, M.H., Lloyd, K.C., Eisenstat, D.D., Lai, C., and Anton E. S. (2006). The role of neuregulin-erbB4 interactions on the proliferation and organization of cells in the adult subventricular zone. Proc. Natl. Acad. Sci. (USA), 103, 1930-1935.
Funes, M., Miller, J.K., Lai, C., Carraway, K.L. III, and Sweeney, C. (2006) The mucin Muc4 potentiates neuregulin signaling by increasing the cell surface population of ErbB2 and ErbB3. J. Biol. Chem., 281, 19310-19319.
Ponomareva, O.N., Fischer, T.M., Lai, C., and Rimer, M. (2006) Schwann cell-derived neuregulin-2? can function as a cell-attached activator of muscle acetylcholine receptor expression. Glia, 54, 630-637.
Woo, R.S., Li, X.M., Tao, Y., Carpenter-Hyland, E., Huang, Y.Z., Weber, J., Neiswender, H., Dong, X.P., Wu, J., Gassmann, M., Lai, C., Xiong, W.C., Gao, T.M. and Mei, L. (2007) Neuregulin-1 enhances depolarization-induced GABA release. Neuron, 54, 599-610.
Ghashghaei, H.T., Lai, C. and Anton, E.S. (2007) Neuronal migration in the adult brain: are we there yet? Nat. Rev. Neurosci., 8, 141-151.
Prieto, A.L., O'Dell, S., Varnum, B., and Lai, C. (2007) Localization and signaling of the receptor protein tyrosine kinase Tyro-3 in cortical and hippocampal neurons. Neuroscience, 150, 319-334.
Brinkmann, B.G., Agarwal, A., Sereda, M.W., Garratt, A.N., Muller, T., Wende, H., Stassart, R.M., Nawaz, S., Humml, C., Velanac, V., Radyushkin, K., Goebbels, S., Fischer, T.M., Franklin, R. J., Lai, C., Ehrenreich, H., Birchmeier, C., Schwab, M.H., and Nave, K.-A. (2008) Neuregulin-1/ErbB signaling serves distinct functions in myelination of the peripheral and central nervous system. Neuron, 59, 581-595.