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Qiang Wu

Assistant Professor of Human Genetics

B.S. Fudan University, China

Ph.D. Cold Springs Harbor Laboratory and SUNY, Stony Brook

Research

References

qiang.wu@genetics.utah.edu

Qiang Wu's Lab Page

Research

How billions of neurons in the vertebrate brain make trillions of precise connections is an intriguing problem. More than a half century ago, Sperry proposed the chemoaffinity hypothesis to explain the mechanism for these specific connections. In particular, he hypothesized that individual neuronal cells carry diverse cytochemical tags that provide synaptic specificity in a "lock-and-key" manner. The Human Genomic Project has now mapped the complete genetic code that determines these complex connections. Recent studies strongly suggest that cadherin family cell adhesion proteins contribute to the molecular diversity required for specifying neuronal cell-cell interactions in the brain. By a combination of computational and experimental approaches, we have identified three closely-linked clusters of protocadherin ( Pcdh ) genes encoding more than fifty cell surface adhesion proteins that may play a role in neuronal connections (Figure 1). Our studies of these cell adhesion genes may provide insights into the normal brain development and abnormal brain tumor formation. Our research on the neural Pcdh genes may, in the long run, contribute to our understanding of many complex neurological diseases, such as schizophrenia and autism.

The main focus in our lab is to characterize three novel Pcdh gene clusters in brain development and function by using multidisciplinary approaches. These Pcdh clusters are vertebrate-specific and are conserved throughout vertebrate evolution (Figure 1). The encoded large number of Pcdh proteins could, in principle, provide the molecular basis for the complexity of cell-cell interactions in the brain. 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. The variable region of each cluster contains more than a dozen of large exons organized in a tandem array. Each variable region exon is preceded by a distinct promoter and is separately spliced to the first constant region exon to generate diverse Pcdh mRNAs. In addition to the extensive alternative splicing, the birth-and-death evolution of variable-exon duplication and mutation also contributes to the diversification of Pcdh genes. The enormous diversity suggests that Pcdh proteins provide a synaptic adhesive code required for establishment and maintenance of complex networks of specific neuronal connections in the brain.

We are investigating the Pcdh gene expression mechanisms and their functional roles in establishing and maintaining specific synaptic connections by a combination of genetics, genomics, biochemical, and molecular approaches. For example, we have targeted several members of the mouse Pcdh cluster with reporters to study their expression patterns and to investigate their functions. These studies will contribute to our understanding of differential cell sorting during embryonic brain development and specific neuronal connection in the adult brain.

We are also interested in bioinformatics and computational sequence analysis. In particular, we are interested in genome-wide mechanisms for sequence diversification and evolution. For example, we found that the genomic organization of the UDP glucuronosyltransferase (UGT1) cluster is strikingly similar to that of the Pcdh clusters. About a dozen highly similar UGT1 variable exons are organized in a tandem array. A common set of four UGT1 constant exons is located downstream from the variable exon tandem array. Each variable exon is separately spliced to the first constant exon to generate diverse UGT1 mRNAs encoding distinct protein isoforms. We also found that the I-branching acetylglucosaminyltransterase cluster has three highly similar variable exons each of which is separately spliced to a common set of downstream constant exons.

 

Comparison of the human (A), chimpanzee (B), mouse (C), rat (D) and zebrafish ( E ) Pcdh clusters. Each cluster contains multiple, highly similar, tandem variable (Var) exons indicated by vertical color bars. Constant (Con) exons are indicated by small red bars following the variable-exon tandem arrays.

References