Study of the molecular mechanisms of alternative splicing. Investigation of splicing regulation by the epithelial-specific splicing factors Esrp1 and Esrp2 during development and disease. Regulation of genome-wide changes in splicing during the epithelial-mesenchymal transition (EMT).
Alternative splicing, Post-transcriptional gene regulation, Epithelial Splicing Regulatory Proteins (ESRPs), Epithelial Mesenchymal Transition (EMT).
Description of Research
The focus of my laboratory is investigation of alternative splicing, whereby a single gene transcript can generate numerous spliced mRNAs, thereby greatly expanding ribonomic and proteomic diversity. Our previous studies focused on alternative splicing of fibroblast growth factor receptor 2 (FGFR2) as a model system. Mutually exclusive splicing of two exons, IIIb and IIIc, gives rise to two functionally different receptors, FGFR2-IIIb and FGFR2-IIIc, in epithelial and mesenchymal cells, respectively. The exquisite cell type-specific expression of these epithelial or mesenchymal specific splice variants is essential during vertebrate development. We identified Epithelial Splicing Proteins 1 and 2 (ESRP1 and ESRP2) in a genome-wide screen for FGFR2 splicing regulators. Subsequent work using RNA-Seq and other systems biology approaches has shown that the ESRPs regulate global programs of alternative splicing to enforce an epithelial cell specific splicing network. We are continuing further investigations into the molecular mechanisms by which the ESRPs regulate alternative splicing. To define the role that the Esrps play in mammalian development we generated mice carrying conditional and/or germline knockout alleles for Esrp1 and Esrp2. Esrp1 knockout (KO) mice displayed bilateral cleft lip associated with cleft palate (CL/P), indicating that it is crucial for normal facial development. Mice with combined KO of both Esrp1 and Esrp2 displayed broader defects in organogenesis. We also determined that conditional ablation of Esrp1 and Esrp2 was associated with an epidermal barrier defect due in part to defects in epithelial cell adhesion and tight junction function. Ongoing studies with these mouse models are using a combination of genetics, developmental biology, and systems biology approaches to understand the mechanisms by which the Esrps function to maintain normal mammalian development and how disruption of Esrp function contributes to disease.
Lab rotations are available in the general area of alternative splicing, protein-RNA interactions, and in further investigation of Esrp1 mediated splicing regulation. Current studies are using mouse genetic models, cell culture models, in vitro approaches, and genome scale investigations. Students are encouraged to contact Dr. Carstens directly to discuss potential rotation projects.
Sungkyoung Lee-Post-doctoral fellow
Natoya Peart-Post-doctoral fellow
Matt Sears-Research Specialist
Lee, S., Cieply, B., Yang, Y., Peart, N., Glaser, C., Chan, P., and R.P. Carstens.*: Esrp1 regulated splicing of Arhgef11 isoforms is required for epithelial tight junction integrity. Cell Reports 25(9): 2417-2430, November 2018.
Rohacek, A.M., Bebee, T.W., Tilton, RK, Radens, C., Barash, Y., Germiller, J.A., Krantz, I.D.*, Carstens, R.P.,* and Epstein, D.J.*. (* Co-corresponding authors): ESRP1 mutations cause hearing loss due to defects in alternative splicing that disrupt cochlear development. Developmental Cell 43(3): 318-331 November 2017
Cieply, B.,Park, J.W., Nakauka-Ddamba, A., Bebee, T., Guo, Y., Shang, X., Lengner, C.J., Xing, Y., and R.P. Carstens: Multiphasic and dynamic changes in alternative splicing during induction of pluripotency are coordinated by numerous RNA binding proteins
Cell Reports 15(2): 247–255, April 2016.
Yang, Y., Park, J.W., Bebee, T.W., Warzecha, C.C., Guo, Y., Shang, X., Xing, Y., and R.P. Carstens
: Determination of a comprehensive alternative splicing regulatory network and
the combinatorial regulation by key factors during the epithelial to mesenchymal transition
Mol. Cell. Biol. 36(11): 1704-1719, June 2016.
Bebee, T. W.,Park, J. W., Sheridan, K. I., Warzecha, C. C., Cieply, B. W., Rohacek, A. M., Xing, Y., and Carstens, R. P.: The splicing regulators Esrp1 and Esrp2 direct an epithelial splicing program essential for mammalian development. eLife 4: e08954, September 2015.
Cieply, B. and Carstens, R.P.: Functional roles of alternative splicing factors in human disease. Wiley Interdiscip Rev RNA 6(3): 311-326, May 2015.
Dittmar, K. A.,Jiang, P.,Park, J. W., Amirikian, K., Wan, J., Shen, S.,Xing, Y., Carstens, R. P.: Genome-wide determination of a broad ESRP-regulated posttranscriptional network by high-throughput sequencing. Mol Cell Biol 32(8): 1468-1482, April 2012.
Warzecha, C.C.,Jiang, P.,Karine Amirikian,K., Dittmar,K.A.,Lu, H., Shen,S., Guo, W.,Xing,Y., and Carstens, R.P..: An ESRP-regulated splicing programme is abrogated during the Epithelial Mesenchymal Transition. EMBO Journal 29(19): 3286-3300, October 2010.
Warzecha, C.C., Sato, T.K., Nabet, B., Hogenesch, J.B., and Carstens, R.P.: ESRP1 and ESRP2 are epithelial cell type-specific regulators of FGFR2 splicing. Molecular Cell 33(5): 591-601, March 2009.
Yang, Y and Carstens, R.P.: Alternative splicing regulates distinct subcellular localization of Epithelial splicing regulatory protein 1 (Esrp1) isoforms. Scientific Reports 7(1): 3848, June 2017.
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Last updated: 05/28/2021
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