Dr. Cathy Savage-Dunn
Ph.D., Columbia University
Office: NSB D-330 – Tel: (718) 997-3440
Laboratory: NSB D-349 – Tel: (718) 997-3403
E-mail: Cathy.SavageDunn@ qc.cuny.edu
Cell-cell signaling is critical to the development and health of multicellular organisms. When cells fail to respond properly to external signals, cells can die prematurely or proliferate inappropriately, leading to diseases such as cancer.
We are interested in understanding how cell signaling regulates animal development. We focus on the TGFβ family of cell signals: a large and evolutionarily conserved class of secreted growth factors. We study TGFβ-related cell signaling using the model organism C. elegans. The nematode (roundworm) C. elegans is an attractive model for the study of cell signaling because of its well-characterized development and cell lineage, as well as the power to apply genetic and molecular biological tools to study signaling pathways in this organism.
Two TGFβ-related signaling pathways have been characterized in C. elegans, the DBL-1 pathway and the DAF-7 pathway. We focus primarily on the DBL-1 pathway (Figure), which regulates body size and male sensory organ patterning (Savage et al., 1996; Gumienny and Savage-Dunn 2013). The components of this pathway and how they interact are highly conserved among species, so that the mechanisms we identify are relevant to the function of TGFβ pathways in vertebrates, including humans. Significantly, the vertebrate homologs of DBL-1 pathway components play a role in the development of cancer, skeletal abnormalities, immune responses, and fat tissue development.
Body size Mutants in the DBL-1 pathway have reduced body size (small phenotype). Although body, organ, and cell sizes are all precisely regulated during animal development, the mechanisms for this control are only beginning to be understood. We have addressed the mechanism of reduced body size in C. elegans DBL-1 pathway mutants. These mutants have a defect in postembryonic but not embryonic growth. Furthermore, the defect in body size is not due to a reduction in cell number, but to reduced cell size. Finally, we have shown that the signaling components function in the hypodermis to regulate body size (Wang et al., 2002). The hypodermis is composed primarily of a single large multinucleated epithelial cell that surrounds the animal and secretes the cuticle.
To identify other candidate TGFβ signal transducers, we conducted a genetic screen for small mutant animals (Savage-Dunn et al., 2003). In this screen, we identified several new genes. The molecular characterization of sma-9 is described below. The molecular characterization of sma-20 is ongoing.
We have also identified potential transcriptional target genes that may mediate DBL-1 regulation of body size (Liang et al., 2007). These target genes include collagen genes, cell cycle control genes, and fat storage and metabolism genes. We are currently investigating the roles of these target genes in body size regulation.
Control of transcription by DBL-1 signaling Smad proteins are conserved TGFβ signal transducers that shuttle from the cytoplasm to the nucleus to regulate target gene transcription. We have studied the role of the SMA-3 Smad C-terminal serine and threonine, the likely sites of phosphorylation and activation by the receptor ser/thr kinase SMA-6. Phosphorylation has previously been hypothesized to be necessary for Smad heteromeric complex formation and nuclear translocation. Our results indicate that phosphorylation is not strictly necessary for nuclear translocation, but is likely necessary for complex formation (Wang et al., 2005). We further uncover a possible role for phosphorylation in protein-protein interactions between Smads and transcriptional cofactors. We are currently interested in identifying the Smad-specific phosphatases that may negatively regulate Smad activity.
In the genetic screen for small mutants, several new genes were identified that are candidate TGFβ signaling components. We have cloned the sma-9 locus (Liang et al., 2003), and found that it encodes the C. elegans homolog of Schnurri, a large zinc finger transcription factor that mediates TGFβ signaling outcomes in Drosophila (fruit fly). SMA-9 is nuclearly localized and may act in concert with the Smads to effect changes in gene transcription in response to dbl-1 signaling. We have found that sma-9 is alternatively spliced, potentially resulting in a variety of protein isoforms with different functions and subcellular localization. We have shown that SMA-9 acts primarily as a transcriptional repressor for body size regulation, but has both transcriptional activator and repressor activities contributing to male tail patterning (Liang et al., 2007).
James Clark, Uday Madaan
Dilshod Khodjaev, Jose Santiago
- Jun Liang Rice (Asst Prof, Borough of Manhattan Community College)
- Marie McGovern (Asst Prof, Kingsborough Community College)
- Rafal Tokarz (Associate Research Scientist, Columbia University)
- Jianjun Wang (Postdoc, Thomas Jefferson University)
- Thilini Fernando (Postdoc, UCLA)
- Edlira Yzeiraj (Medical Resident, Cleveland Clinic)
- Jianghua Yin
- Sheng Xiong
Gumienny, T.L., and C. Savage-Dunn. 2013. TGF-β signaling in C. elegans. WormBook, ed. The C. elegans Research Community, doi/10.1895/wormbook.1.22.2, http://www.wormbook.org.
Fernando, T., S. Flibotte, S. Xiong, J. Yin, E. Yzeiraj, D.G. Moerman, A. Meléndez and C. Savage-Dunn. 2011. C. elegans ADAMTS ADT-2 regulates body size by modulating TGFβ signaling and cuticle collagen organization. Dev. Biol., 352:92-103.
Savage-Dunn, C., L. Yu, K. Gill, M. Awan, T. Fernando. 2011. Nonstringent tissue-source requirements for BMP ligand expression in regulation of body size in Caenorhabditis elegans. Genetics Research, 93:427-432.
Yin, J., L. Yu and C. Savage-Dunn. 2010. Alternative trans-splicing of Caenorhabditis elegans sma-9/schnurri generates a short transcript that provides tissue-specific function in BMP signaling. BMC Molecular Biology, 11:46.
McGovern, M., L. Yu, M. Kosinski, D. Greenstein and C. Savage-Dunn. 2007. A Role for Sperm in Regulation of Egg-Laying in the Nematode C. elegans. BMC Developmental Biology, 7:41.
Liang, J., L. Yu, J. Yin, and C. Savage-Dunn. 2007. Transcriptional Repressor and Activator Activities of SMA-9 Contribute Differentially to BMP-Related Signaling Outputs. Developmental Biology,305:714-725.
Liang, J., R. Lints, M.L. Foehr, R. Tokarz, L. Yu, S.W. Emmons, J. Liu, and C. Savage-Dunn. 2003. The Caenorhabditis elegans schnurri homolog, sma-9, mediates stage- and cell type-specific responses to dbl-1 BMP-related Signaling. Development, 130:6453-6464.
Savage-Dunn, C., L.L. Maduzia, C.M. Zimmerman, A.F. Roberts, S. Cohen, R. Tokarz and R.W. Padgett. 2003. A Genetic Screen for Small Body Size Mutants in C. elegans Reveals Many TGFβ Pathway Components. genesis 35:239-247.
Wang, J., R. Tokarz and C. Savage-Dunn. 2002. The expression of TGFβ signal transducers in the hypodermis regulates body size in C. elegans. Development 129:4989-4998.
Savage, C., P. Das, A.L. Finelli, S.R. Townsend, C.Y. Sun, S.E. Baird and R.W. Padgett 1996. Caenorhabditis elegans genes sma-2, sma-3, and sma-4 define a conserved family of transforming growth factor β pathway components. Proc. Natl. Acad. Sci. 93:790-794.