Genetic Analysis of Protocadherin Diversity in the Central Nervous System

The human brain is a massive network of over 100 billion neurons with extraordinary complexity. The function of the neural network relies on precise patterns of neuronal connections. How does a neuron recognize its target(s) and establish correct synaptic contacts? My laboratory is interested in understanding the molecular basis for the precision and complexity of neuronal circuitry in the brain.

Our present work is focused on a large family of newly identified cell adhesion molecules, protocadherins (Pcdhs). The vertebrate Pcdh genes (14 Pcdha, 22 PcdhB and 22 Pcdhy in mouse) have a unique genomic organization that is similar to that of the immunoglobulin gene. These genes consist of “variable” and “constant” exons orientated in a tandem array on a single chromosome and can generate a significant number of diverse cell adhesion molecules through a combination of cell-specific promoter activation and cis- alternative splicing. The expression studies on Pcdh mRNAs and proteins have led to speculation that combinatorial patterns of Pcdh expression might underlie precise patterns of neuronal connectivity. Our initial analyses on Pcdh? null mice and other Pcdhy mutant mice have provided evidence that Pcdhy is essential for vertebrate neural development and may play a role in certain aspects of synaptogenesis.

To understand the molecular and cellular mechanisms of Pcdhy’s function in the development of the vertebrate central nervous system, we have generated multiple genetically modified Pcdhy mouse models. The combination of these genetic tools with biochemical and cell biological approaches provides us a powerful way to dissect the Pcdh? signaling system and determine its role in establishing neuronal connectivity. Ultimately our studies may shed light on how combinatorial surface molecular codes contribute to the specificity and complexity of the neuronal network.

Wang, X., Weiner, J.A., Levi, S., Craig, A-M., Bradley, A. and Sanes, J.R. Gamma protocadherins are required for survival of spinal interneurons. Neuron. 36, 843-854, 2002.

Wang, X., Su, H, and Bradley, A. Molecular mechanisms governing Pcdh y gene expression: evidence for a multiple promoters and cis- alternative splicing model. Genes & Development 16: 1890-1905, 2002.

Wang, X., Su, H., Copenhagen, L.D., Vaishnav, S., Pieri,F., Shope, C.D., Brownell, W.E., De Biasi, M., Paylor, R. and Bradley, A. Urocortin deficient mice display normal stress-induced anxiety behavior and autonomic control but impaired acoustic startle response. Mol. Cell. Biol. 22, 6605-6610, 2002

Xue, Y.,Wang, X., Li, Z., Gotoh, N., Chapman, D. and Skolnik, E.Y. Mesodermal patterning defect in mice lacking the Ste20 NCK interacting kinase (NIK). Development 128, 1559-1572, 2001

Urano, F., Wang, X., Bertolotti, A., Zhang, Y., Chung, P. Harding, H.P. and Ron, D. Coupling of Stress in the Endoplasmic Reticulum to Activation of JNK Protein Kinases by Transmembrane Protein Kinase IRE1. Science 287, 664-666, 2000.

Su, H., Wang, X. and Bradley, A. Nested chromosomal deletions induced with retroviral vectors in mice. Nature Genetics 24, 92-95, 2000.

Wang, X., Jolicoeur, E.M., Conte, N., Chaffanet, M., Zhang, Y., Mozziconacci, M.-J., Finer, H., Birnbaum, D., Pebusque, M.-J., and Ron, D. ?-heregulin is the product of a chromosomal translocation fusing the DOC4 and HGL1/NRG1 genes in the MDA-MB-175 breast cancer cell line. Oncogene 18, 5718-5721, 1999.

Wang, X., Harding, H. P., Zhang, Y., Jolicoeur, E., Kuroda, M., and Ron, D. Cloning of mammalian Ire1 reveals diversity in the ER stress responses. EMBO J. 17, 5708-5717, 1998.

Wang, X., Kuroda, M., Sok, J., Kimmel, R., Batchvarova, N., Zinszner, H., and Ron, D. Identification of novel stress-induced genes downstream of chop. EMBO J. 17, 3619-3630, 1998.

Wang, X., Lawson, B., Brewer, J., Zinszner, H., Sanjay, A., Mi, L., Boorstein, R., Kreibich, G., Hendershot, L., and Ron, D. Signals from the stressed endoplasmic reticulum induce C/EBP homologous protein (CHOP/GADD153). Mol. Cell. Biol. 16, 4273-4280, 1996.

Wang, X., and Ron, D. Stress-induced phosphorylation and activation of the transcription factor CHOP (GADD153) by p38 MAP-kinase. Science 272, 1347-1349, 1996.

View all publications by publications by Alec Wang listed in the National Library of Medicine (PubMed).