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Research Summary
The main focus in our lab is to characterize three novel Pcdh gene clusters in brain development and function by using multidisciplinary approaches. We have identified more than fifty Pcdh genes that are expressed in the mammalian brain. These neural Pcdh genes 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. The variable region of each cluster contains more than a dozen of large exons organized in a tandem array. Each variable region exon is separately spliced to the first constant region exon to generate diverse Pcdh mRNAs. 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 their 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 DNA sequence analyses to identify patterns of genomic organizations in mammalian genomes. For example, we found that the genomic organization of the UDP clucuronosyltransferase (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. Finally, we found several additional genes that have about a dozen variable first exons arranged in tandem and a common set of downstream constant exons; however, their variable exons do not display sequence similarity. We conclude that the variable and constant organization is more prevalent in the mammalian genome than previously thought, and provides a genomic framework for directing distinct cell- and tissue-specific patterns of gene expression.

Research Summary

The main focus in our lab is to characterize three novel Pcdh gene clusters in brain development and function by using multidisciplinary approaches. We have identified more than fifty Pcdh genes that are expressed in the mammalian brain. These neural Pcdh genes 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. The variable region of each cluster contains more than a dozen of large exons organized in a tandem array. Each variable region exon is separately spliced to the first constant region exon to generate diverse Pcdh mRNAs. 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 their 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 DNA sequence analyses to identify patterns of genomic organizations in mammalian genomes. For example, we found that the genomic organization of the UDP clucuronosyltransferase (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.

Finally, we found several additional genes that have about a dozen variable first exons arranged in tandem and a common set of downstream constant exons; however, their variable exons do not display sequence similarity. We conclude that the variable and constant organization is more prevalent in the mammalian genome than previously thought, and provides a genomic framework for directing distinct cell- and tissue-specific patterns of gene expression.