QIANG WU

email: qiang.wu@genetics.utah.edu		 Assistant Professor of Human Genetics

Wu Laboratory Home page
Molecular Neurobiology

B.S. 1990, Fudan University; M.S. 1993, Fudan University, Ph.D. 1998, Cold Spring Harbor Laboratory and SUNY at Stony Brook; Postdoctoral Fellow, 1998-2001, Harvard University.

RESEARCH:

A central problem in understanding brain development and function is determining how diverse neurons establish specific connections to form complex synaptic circuitry. Cadherins, a superfamily of diverse transmembrane glycoproteins, may play an essential role in specific cell-cell interactions during embryonic brain development and in the adult brain. Certain members of the cadherin family have been shown to function in synaptic adhesion, axon outgrowth and guidance, and synaptic plasticity. The cadherin family proteins can be divided into two distinct subfamilies: the classic cadherin and the protocadherin proteins. We are interested in characterizing three novel protocadherin gene clusters in brain development and function by using multidisciplinary approaches.

By a combination of computational and experimental approaches, we have identified more than fifty protocadherin genes that are expressed in the brain. These neural protocadherin genes could, in principle, provide the molecular basis for the complexity of cell-cell interactions in the brain. These genes are organized into three closely linked clusters. The genomic sequences of two of the three clusters have both "variable" and "constant" regions, providing an unusual organization similar to that of immunoglobulin and T cell receptor gene clusters. Each variable region exon is separately spliced to constant region exons to generate diverse protocadherin mRNAs. This unusual organization suggests that a novel mechanism may be involved in the generation of protocadherin diversity and their cell-specific expression patterns in the brain. The enormous diversity suggests that protocadherins provide a synaptic adhesive code required for establishment and maintenance of complex networks of specific neuronal connections in the brain.

We are interested in understanding the molecular mechanism of protocadherin expression and regulation in the brain. Members of one protocadherin cluster have been shown to express at synaptic junctions in different region of the adult brain, and individual neurons appear to express a distinct subset of the cluster. The mechanism of cell-specific protocadherin gene expression in the brain is poorly understood. Comparative genomics studies suggest that each variable region exon is associated with a distinct promoter. Therefore, cell-specific protocadherin expression may be determined by a combination of differential promoter activation and alternative splicing. We will characterize variable-region promoters to understand their differential activation. We hope to define the splicing mechanism of cell-specific protocadherin expression in an effort to characterize their regulation in the brain.

We are also interested in investigating the role that the protocadherin played in establishing and maintaining specific synaptic connections. We are generating protocadherin antibodies to detect the protein localization in neurons in different regions of the brain. These antibodies will allow us to identify the interacting proteins through biochemical experiments in order to study the role of protocadherin signal transduction pathway in brain neuron migration. We will establish a cell aggregation assay in tissue culture cells to investigate the cell adhesion properties of protocadherin proteins. These studies will contribute to our understanding of differential cell sorting during embryonic brain development and specific neuronal connection in the adult brain. Because the cell adhesion properties are altered in tumorigenesis, these studies may also contribute to our understanding of brain tumor metastasis.

Selected Publications

Wu, S., Ying, G., Wu, Q., and Capecchi, M.R. (2007) Towards simpler and faster genome-wide mutagenesis in mice. Nature Genetics, Published online: 17 June 2007; doi:10.1038/ng2060.

Li, C. and Wu, Q. (2007) Evolution of vertebrate multiple variable first exons and structural diversity of drug metabolizing enzymes. BMC Evolutionary Biology, 7:69 (Published online on May 2, 2007).

Zou, C., Huang, W., Ying, G., and Wu, Q. (2007) Sequence analysis and expression mapping of the rat clustered protocadherin gene repertoires. Neuroscience, 144:579-603.

Wu, Q. (2005) Comparative genomics and diversifying selection of the clustered vertebrate protocadherin genes. Genetics, 169:2179-2188.

Zhang, T., Haws, P., and Wu, Q. (2004) Multiple variable first exons: a mechanism for cell- and tissue- specific gene regulation. Genome Research, 14:70-89.

Tasic, B., Nabholz, C.E., Baldwin, K.K., Kim, Y., Rueckert, E.H., Ribich, S.A., Cramer, P., Wu, Q., Axel, R., and Maniatis, T. (2002) Promoter choice determines splice site selection in protocadherin a and g pre-mRNA splicing. Mol. Cell., 10:21-33.

Wu, Q., Zhang, T., Cheng, J.-F., Kim, Y., Grimwood, J., Schmutz, J., Dickson, M., Noonan, J.P., Zhang, M.Q., Myers, R.M., and Maniatis, T. (2001) Comparative DNA sequence analysis of mouse and human protocadherin gene clusters. Genome Res., 11:389-404.

Wu, Q., and Maniatis, T. (2000) Large exons encoding multiple ectodomains are a characteristic feature of protocadherin genes. Proc. Natl. Acad. Sci. USA, 97:3124-3129.

Pohl, U., Smith, J.S., Tachibana, I., Ueki, K., Lee, H.K., Ramaswamy, S., Wu, Q., Mohrenweiser, H.W., Jenkins, R.B., and Louis, D.N. (2000) EHD2, EHD3, and EHD4 encode novel members of a highly conserved family of EH domain-containing proteins. Genomics, 63:255-262.

Wu, Q., and Maniatis, T. (1999) A striking organization of a large family of human neural cadherin-like cell adhesion genes. Cell, 97:779-790.

Wu, Q., and Krainer, A.R. (1999) AT-AC pre-mRNA splicing mechanisms and conservation of minor introns in voltage-gated ion channel genes. Molecular and Cellular Biology, 19:3225-3236.

Wu, Q., and Krainer, A.R. (1998) Purine-rich enhancers function in the AT-AC splicing pathway and do so independently of intact U1 snRNP. RNA, 4:1664-1673.

Wu, Q., and Krainer, A.R. (1997) Splicing of a divergent subclass of AT-AC introns requires the major spliceosomal snRNAs. RNA, 3:586-601.

Wu, Q., and Krainer, A.R. (1996) U1-mediated exon definition interactions between AT-AC and GT-AG introns. Science, 274:1005-1008.

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