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Molecular and Cellular Biology

Houston, Texas

Image 1: Ovulated mouse cumulus cell oocyte complex immunostained for matrix proteins hyaluronan and versican. By JoAnne Richards, Ph.D.; Image 2: By Yi LI, Ph.D.; Image 3: Mouse oocyte at meiosis I immunostained for tubulin (red) phosphop38MAPK (green) and DNA (blue). By JoAnne Richards, Ph.D.; Image 4: Expanded cumulus cell ooctye ocmplex immunostained for hyaluronan (red), TSG6 (green) and DAN (blue). By JoAnne Richards, Ph.D.; Image 5: Epithelial cells taken from a mouse mammary gland were cultured in a dish and transduced with a retrovirus expressing two genes. The green staining shows green fluorescent protein and the red staining shows progesterone receptor expression. The nucleus of each cell is stained blue. Photomicrograph taken at 200X magnification. By Sandra L. Grimm, Ph.D.; Image 6: Ovarian vasculature (red) is excluded from the granulosa cells (blue) within growing follicles (round structures); Image 7: Ovulated mouse cumulus cell oocyte complex immunostained for matrix proteins hyaluronan and versican. By JoAnne Richards, Ph.D.
Department of Molecular and Cellular Biology
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Thomas A Cooper, M.D.

Thomas A Cooper, M.D. photoS. Donald Greenberg Professor of Pathology

Professor
Department of Molecular and Cellular Biology

Education

M.D.: Temple University Medical School, Philadelphia
Postdoctoral training: University of California, San Francisco

Research Interest

Alternative Splicing Regulation in Development and Disease
Up to seventy six percent of human genes express multiple mRNAs by alternative splicing of their pre-mRNAs. As a result, individual genes express multiple protein isoforms which can exhibit strikingly different functions. Alternative splicing is often regulated according to cell-specific patterns based on differentiated cell type, developmental stage, or in response to an external signal. Therefore, alternative splicing not only generates an extremely diverse human proteome from a relatively small number of genes but it also directs regulated expression of these proteins in response to a wide range of cues.

We are interested in understanding the mechanisms of splicing regulation, from how regulatory proteins tell the basal machinery whether to include or skip an exon to the signaling events that coordinate splicing changes during development.

We work on two families of splicing regulators (called CELF and MBNL proteins) which regulate splicing directly by binding to specific sequence motifs within pre-mRNAs. One question being addressed is, how does binding of a positive splicing regulator recruit or stabilize binding of the basal splicing machinery? Proteins that interact with the splicing regulators, either directly or by association in an activation complex, will be identified.

A large variety of splicing changes are developmentally regulated. Another goal is to determine how the activities of the splicing regulators are modified during development and to identify the signaling pathways responsible for their modification. We are also investigating the regulatory networks responsible for coordination of developmentally regulated splicing.

A separate area of investigation is the pathogenic mechanism of myotonic dystrophy (DM1), a dominantly inherited disease caused by an expanded CTG trinucleotide repeat in the 3' untranslated region of the DMPK gene. RNAs expressed from the expanded allele that contain long tracts of CUG repeats accumulate in the nucleus and disrupt alternative splicing. The mechanism is unknown but it involves disrupted functions of the CELF and MBNL proteins. We are using bioinformatic, biochemical, and molecular approaches to identify pre-mRNA targets of CELF and MBNL proteins whose mis-regulated splicing contributes to severe manifestations of disease. Transgenic mouse models that inducibly express CELF proteins or CUG repeat RNA are being used to investigate the mechanisms of pathogenesis and will be used to test treatment regimes.

Contact Information

Baylor College of Medicine
One Baylor Plaza, Cullen 268B
Houston, TX 77030

Phone: 713-798-3141
E-mail: tcooper@bcm.edu
Lab Web Site: www.bcm.edu/pathology/labs/cooper/index.htm

Selected Publications

  1. Cooper TA, Wan L, and Dreyfuss G (2009). RNA and disease. Cell 136, 777–793.
  2. Kalsotra A, Tran D, Ward A, Xiao X, Burge CB, Castle JM, Johnson, JC, and Cooper TA (2008). A conserved program of regulated alternative splicing during vertebrate heart development. Proc. Nat’l Acad. Sci. 105, 20333-20338.
  3. Castle JC, Zhang C, Shah JK, Kulkarni AV, Kalsotra A, Cooper TA, and Johnson JM (2008). Differential expression of 24,426 human alternative splicing events and predicted cis-regulation in 48 tissues and cell lines. Nat. Genet. 40, 1416-1425.
  4. Orengo JP, Chambon P, Metzger D, Mosier DR, Snipes GJ, and Cooper TA (2008). Expanded CTG repeats within the DMPK 3’ UTR causes severe skeletal muscle wasting in an inducible mouse model for myotonic dystrophy. Proc. Nat’l Acad. Sci. 105, 2646-2651.
  5. Kuyumcu-Martinez NM, Wang GS, and Cooper TA (2007). Increased steady state levels of CUG-BP1 in Myotonic Dystrophy 1 are due to PKC-mediated hyper-phosphorylation. Mol. Cell 28, 68-78.
  6. Wang GS, Kearney DL, De Biasi M, Taffet GE, and Cooper TA (2007). Elevation of RNA-binding protein CUGBP1 is an early event in an inducible heart-specific mouse model of myotonic dystrophy. J. Clin. Invest. 117, 2802-2811.
  7. Wang GS and Cooper TA (2007). Splicing in disease: disruption of the splicing code and the decoding machinery. Nature Rev. Genet. 8, 749-761.
  8. Bland CS and Cooper TA (2007). Micromanaging alternative splicing during muscle differentiation. Dev Cell 12, 171-172
  9. Ranum LP and Cooper TA (2006). RNA-mediated neuromuscular disorders. Ann. Rev. Neuroscience 29, 259-277.
  10. Cooper TA (2006). A reversal of fortune for myotonic dystrophy? N. Engl. J. Med. 355, 1825-1827.

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