Cell-cell communication is essential for the proper manifestation of many events that take place during the development of multi-cellular organisms, including fate specification, cell shape change and migration, growth, and differentiation. We are interested in the underlying molecular mechanisms that mediate cell signaling during these developmental events, as well as the developmental consequences associated with signaling dysfunction. Throughout my career I have merged the use of genetic manipulation with cell and molecular analyses to dissect complex processes revealing how cells interact.  We are particularly interested in the regulation of signaling output by the BMP pathway. Central to our research has been an elucidation of the molecular mechanisms underlying the regulation of this potent signaling pathway. Our research in the Drosophila model system has led to new discoveries with regard to regulating ligand production and differential receptor contribution in the signaling complex.  We are currently applying these findings to studies of ALS, cleft lip and/or palate and fibrodysplasia ossificans progressiva (FOP). 

The goal of the research in our laboratory is to understand how signaling molecules facilitate the communication between cells. Cellular communication is essential for the proper manifestation of cell fate specificcation, cell movements, growth, and differentiation during the development of multi-cellular organisms. Secreted proteins, such as those which belong to the transforming growth factor-B/bone morphogenetic proteins (TGF-B/BMP ) family of signaling molecules, mediate intercellular communication through their binding and/or association to integral membrane proteins. As a resulting of ligand-receptor interactions, the transduced signal ultimately culminates in the activation or repression of gene expression in the responding cell. As such, alterations in the cell's physiology, phenotype, position in the cell cycle, and the expression of new sets of genes and proteins, result. TGF-B/BMP proteins are found in both vertebrates and invertebrates and act as signaling ligands instrumental in the control of many developmental processes, as well as in homeostasis in the adult. To understand how this highly conserved signaing pathway influences diverse cellular events, we have elucidated specific molecular mechanisms responsible for regulating signaling output.  We primarily exploit genetic, molecular, cell biological, and behavioral approaches in both Drosophila and mouse, to investigate the function and regulation of these molecules in vivo, in the context of the whole organism.   Defects in cell signaling are often associated with developmental abnormalities and a diseased state. We have applied our knowledge of cell signaling in the normal context of development to study disruptions in cell signaling in fibrodysplsia ossificans progressiva (FOP), cleft lip/palate (CL/P), and most recently, amyotrophic lateral sclerosis (ALS). 

CURRENT

ALS: Finding a Cure

Title: Accelerating identification of cross-species suppressor genes and elucidating early pathophysiology in ALS

Role in project: co-PI

Award dates: Nov 1, 2015 – Oct 31, 2018

 

Biogen idec MA Inc

Title: SOD1-based ALS: Identification of biomarkers and therapeutics

Role in project: PI

Award dates: January 1, 2015 – Dec 31, 2017

 

PAST

The Judith and Jean Pape Adams Foundation

Title: Elucidating cellular dysfunction in ALS and restoring function

Role in project: PI

Award dates: Dec 31, 2014 – Dec 31, 2015

Cleft Palate Foundation

Title: Impact of hBMP4 mutations on craniofacial development

Role in project: PI

Award dates: 7/1/2015 – 6/30/2016

Co-PIs: Helena Taylor, Asst. Prof. Surgery and Pediatrics, Stephen Sullivan, Asst. Prof. Surgery and Pediatrics, Warren Alpert Medical School, Brown University

Emerging Areas of New Science DEANS Award

Title: Importance of BMP processing in craniofacial development

Role in project: PI

Co-PIs: Helena Taylor, Asst. Prof. Surgery and Pediatrics, Stephen Sullivan, Asst. Prof. Surgery and Pediatrics, Warren Alpert Medical School, Brown University

Award dates: July 1, 2014 – June 30, 2015 

National Institutes of Health - 2R01 GM068118-05

Title of project: Differential regulation of BMP signals in vivo

Role in project: PI

Project dates: 07/01/2011 – 06/30/2015

Cali Center Development Grant

Center for FOP Research and Related Disorders - University of Pennsylvania

Total project period: 02/01/2010 - 01/31/2011

Role in project: PI

Title of project: FOP in Drosophila: Playing (the) Sax and ACVR1 to decipher the tune

Center for FOP Research and Related Disorders - University of Pennsylvania

Total project period: 06/01/2007 – 10/31/2009

Role in project: PI

Title of project: FOP in Drosophila: Playing (the) Sax and ACVR1 to decipher the tune

Richard B. Salomon Faculty Research Award
Brown University
Office of the Vice President for Research
Total project period: 02/01/2004-–07/01/2005
Role in project: PI
Title of project: "Establishing assays to investigate BMP ligand type and receptor choice"

NIH/NCRR - 1 P20 RR15578-01
COBRE
Center for Genetics and Genomics (Sedivy, J.-PI)
Total project period: 09/30/2000–-08/31/2005
Role in project: Investigator (K. Wharton)
Title of project: "Mechanism of BMP signaling"

American Cancer Society - RPG DDC-98790
Total project period: 07/01/1999-06/30/2002
Title of Project: "Functional analysis of signaling by multiple TGF-/BMP ligands"

National Science Foundation - IBN-9604769
Total project period: 03/15/1997-08/31/1999
Title of Project: "Analysis of TGF-/BMP-mediated Signaling"

American Heart Association - Established Investigatorship 94002580
Total project period: 07/01/1994-06/30/1999
Title of project: "Functional Analysis of TGF--mediated Cellular Signaling"

Salomon Faculty Research Award
Total project period: 02/01/1996-01/31/1997
Title of project: "TGF-β-mediated signaling during oogenesis"

National Science Foundation - IBN-9205808
Total project period: 09/01/1992-08/31/1996
Title of project: "Cellular communication during Drosophila development"

American Cancer Society - DB-32
Total project period: 01/01/1993-12/31/1995
Title of project: "TGF- cell signaling during development"

NECUSE –The New England Consortium for Undergraduate Science Education/
The Pew Charitable Trusts
Support for two Brown undergraduates to attend Annual Drosophila Conference
Awarded: 12/13/1993

American Cancer Society - Institutional Award
Total project period: 08/01/1991-06/30/1993
Title of project: "Functional analysis of a TGF--like gene during development"

Sahin, A., Held, A., Bredvik, K., Major, P., Achilli, T-M., Kerson, A.G., Wharton, K., Stilwell, G., Reenan, R. (2017) Human SOD1 ALS mutations in a Drosophila knock-in model cause severe phenotypes and reveal dosage-sensitive gain- and loss-of-function components. Genetics 205, 707-723. 

James, R.E., Hoover, K.M., Bulgari, D., McLaughlin, C.N., Wilson, C.G., Wharton, K.A., Levitan, E.S., Broihier, H.T. (2014) Crimpy enables discrimination of presynaptic and postsynaptic pools of a BMP at the Drosophila neuromuscular junction. Developmental Cell 31, 586-598. PMCID: PMC4283799

Wharton, K.A. and Serpe, M. (2013) Fine tuned shuttles for bone morphogenetic proteins.  Curr Opin Genet Dev 23, 374-384. PMCID: PMC3760970 (invited review)

Boulanger, A., Farge, M., Ramanoudjame, C., Wharton, K., Dura, J-M. (2012) Drosophila motor neuron retraction during metamorphosis is mediated by inputs from TGF-b/BMP signaling  and orphan nuclear receptors. PLoS ONE 7(7): e40255. doi:10.1371/journal.pone.0040255. PMCID: PMC339-346

Akiyama, T., Marqués, G. and Wharton, K.A. (2012) Conserved unconventional proconvertase processing site produces a large bioactive BMP ligand with signaling properties distinct from the conventional C-terminally derived ligand. Science Signalling 5, ra28.  PMCID: PMC3699424

Le, V.Q. and Wharton, K.A. (2012) Hyperactive BMP signaling induced by ALK2R206H requires type II receptor function in a Drosophila model for classic Fibrodysplasia Ossificans Progressiva. Developmental Dynamics 241, 200-214. (Special Issue: Drosophila as a model for understanding development and disease) PMCID: PMC3454517

Ballard, S., Jarolimova, J. and Wharton, K.A. (2010) Gbb/BMP signaling is required to maintain energy homeostasis in Drosophila.  Developmental Biology 337, 375-85. PMCID: PMC2838617

Twombly, V., Bangi, E., Le, V.Q., Malnic, B., Singer, M. and Wharton, K.A. (2009).  Functional analysis of saxophone, the Drosophila BMP type I receptor ortholog of human ALK1/ ACVRL1 and ACVR1/ALK2. Genetics 183, 563-79. PMCID: PMC2766317

Wharton, K.A. and Derynck, R. (2009) TGF-β family signaling: Novel insights in development and disease. Development 136, 3691-97. PMID: 19855012 

Prabhat, Forsberg, A., Katzourin, M., Wharton, K.A. and Slater, M (2007).  A Comparative Study of Desktop, Fishtank and Cave Systems for the Exploration of Volume Rendered Confocal Data Sets. IEEE Transactions on Visualization and Computer Graphics, epub. 06 Aug 2007. http://doi.ieeecomputersociety.org/10.1109/TVCG.2007.70433

Bangi, E. and Wharton, K. A. (2006). Dual function of the Drosophila ALK1/ALK2 orthologue, Saxophone, influences the BMP activity gradient critical for wing patterning. Development 133, 3295-3303.  PMID: 16887821

Bangi, E. and Wharton, K.A. (2006) Dpp and Gbb exhibit different effective ranges in the establishment of the BMP activity gradient critical for Drosophila wing patterning. Developmental Biology 295, 178-193.  PMID: 16643887

Sinenko, S.A., Kim, E.K., Wynn, R., Manfruelli, P., Ando, I., Wharton, K.A., Perrimon, N. and Mathey-Prevot, B. (2004). Yantar is a novel and evolutionary conserved gene involved in Drosophila hemocyte differentiation. Developmental Biology 273: 48-62. 

Ray, R.P. and Wharton, K.A. (2001) Twisted perspective: New insights into extracellular modulation of BMP signaling during development. Cell 104, 801-804. 

Ray, R. and Wharton, K.A. (2001) Context-dependent relationships between the BMPs gbb and dpp during development of the Drosophila wing imaginal disc. Development 128, 3913-3925.  PMID: 11641216

Wharton, K. A., Cook, J., Torres-Schumann, S., de Castro, K., Borod, E., Phillips, D. A., (1999). Genetic analysis of the BMP-related gene, gbb, identifies multiple requirements during Drosophila development. Genetics 152: 629-40. PMID: 10353905

Haerry, T. E., Khalsa, O., O'Connor, M. B., Wharton, K. A., (1998). Synergistic signaling by two BMP ligands through the SAX and TKV receptors controls wing growth and patterning in Drosophila. Development 125: 3977-87. PMID: 9735359

Khalsa, O., Yoon, J-W., Torres-Schumann, S., Wharton, K.A., (1998). TGF-β/BMP superfamily members, Gbb-60A and Dpp,cooperate to provide pattern information and establish cell identity in the Drosophila wing. Development 125: 2723-34. PMID: 9636086

Wharton, K.A., Ray, R.P., Findley, S.D., Duncan, H.E. and Gelbart, W.M. (1996) Molecular lesions associated with alleles of decapentaplegic identify residues necessary for TGF-β/ BMP cell signaling in Drosophila melanogaster. Genetics 142, 493-505. PMID: 8852848

Raftery, L.A., Twombly, V., Wharton, K.A. and Gelbart, W.M. (1995) Genetic screens to identify elements of the decapentaplegic signaling pathway in Drosophila. Genetics 139, 241-54. PMID: 7705627

Wharton, K. A. (1995) How many receptors does it take? Bioessays 17, 13-16.

Wharton, K.A., Ray, R. and Gelbart, W.M. (1993) An activity gradient of decapentaplegic is required for dorsal-ventral patterning in the Drosophila embryo. Development 117, 807-22. PMID: 8330541

Wharton, K.A., Thompsen, G.and Gelbart, W.M. (1991) Drosophila 60A gene, a TGF-β family member, is closely related to human bone morphogenetic proteins. PNAS 88, 2914-18. PMID: 1924384

Ramos, R.G.P., Grimwade, B.G., Wharton, K.A., Scottgale, T.N. and Artavanis-Tsakonas, S. (1989) Physical and functional definition of Drosophila Notch locus by P -element transformation. Genetics 123, 337-48. PMID: 2555253

Yedvobnick, B., Muskavitch, M.A.T., Wharton, K.A., Halpern, M.E., Paul, E., Grimwade, B.G., and Artavanis-Tsakonas, S. (1985) Molecular genetics of Drosophila neurogenesis. Cold Spring Harbor Sympos.Quant.Biology 50:841-854.

Artavanis-Tsakonas, S., Grimwade, B., Halpern, M.E., Johansen, K. Markopoulou, K., Ramos, R.G.P. Schlesinger-Bryant, R., Wharton, K.A. and Yedvobnick, B. (1985) Molecular biology of genes involved in the neurogenesis of Drosophila. Society for Developmental Biology 44th Annual Symposium. ed. Joseph Gall

Wharton, K.A., Johansen, K.M., Xu, T. and Artavanis-Tsakonas, S. (1985) Nucleotide sequence from the neurogenic locus Notch implies a gene product which shares homology with proteins containing EGF-like repeats. Cell 43, 567-81. PMID: 3935325

Wharton, K.A., Yedvobnick,B., Finnerty, V.G. and Artavanis-Tsakonas, S. (1985) opa: A novel family of transcribed repeats shared by the Notch locus and other developmentally regulated loci in Drosophila melanogaster. Cell 40: 55-62. PMID: 2981631

Artavanis-Tsakonas, S., Grimwade, B.G., Harrison, R.G., Markopoulou, K.,Muskavitch, M.A.T., Schlesinger-Bryant, R., Wharton, K.A. and Yedvobnick, B. (1984) The Notch locus of Drosophila melanogaster: A molecular analysis. Developmental Genetics 4: 233-254.

Mooseker, M.S., Bonder, E.M., Grimwade, B.G., Howe, C.L., Keller, T.C.S., Wasserman,R.H. and Wharton, K.A. (1982) Regulation of contractility, cytoskeletal structure and filament assembly in brush borders of the intestinal epithelial cells. Cold Spring Harbor Sympos.Quant.Biology 46: 855-870.

Mooseker, M.S., Pollard, T.D. and Wharton, K.A. (1982) Nucleated polymerization of actin from the two ends of microvillar filaments in the intestinal brush border. J.Cell Biol. 95:223-233.

NIH NRSA Training grant in Genetics, 1982-1986
Sessil B. Anonymous Fellowship, Yale University, 1986-87
EMBO Short Term Fellowship, IMBB, Crete, Greece, 1987
NIH NRSA Postdoctoral Fellowship, Harvard University, 1988-1991
American Heart Association Established Investigatorship, Brown University, 1994-1999
Manning Assistant Professor, Brown University, 2000
Elizabeth H. Leduc Award for Excellence in Teaching in the Life Sciences, Brown University, 2005

Visiting Scientist, Department of Cell Biology, Biozentrum, University of Basel, Switzerland (sabbatical leave from Brown University, Spr 2003)

Visiting Scientist, Departement Genetique et Developpement, Institut de Genetique Humaine, CNRS Montpellier, France (sabbatical leave from Brown University, Spr 2010)

Meeting organizer: BMP Boston: 11^th International BMP Conference, Boston, USA,  2016

Member: National Institutes of Health – Center for Scientific Review – ZRG1 CB PO2 Study Section, 2014

Member: National Institutes of Health – Center for Scientific Review - ZRG1 FO5-R Study Section, 2011

Member: National Institutes of Health – Center for Scientific Review - DEV2 Study Section, 2007, 2009 

Member: National Institutes of Health – Center for Scientific Review SEP, ZRG1 BDA-A (02), 2006

Panel member: Academy of Finland, Biosciences panel, Helsinki,  2005
Panel member: American Cancer Society – Peer Review Committee on Development, Differentiation, and Cancer, Jan. 1, 2001–- Dec. 31, 2005
Memberships: Genetics Society of America, Sigma Xi, Society of Developmental Biology, Society for Neuroscience, ASBMB

 

BIOL1310/2310 Developmental Biology – lecture course with weekly labs intended for intermediate to advanced undergraduate and grad students. Course covers a broad range of topics with an emphasis on conceptual learning and critical thinking. In this fast moving field, new lecture material is added each year with new readings from the primary literature. Live embryo laboratories provide students with the unique opportunity to perform classical experiments, as well as employ new techniques in embryo manipulations. We use digital lab notebooks which has had a major impact on student learning and scientific investigation, as individuals become more engaged with the material while benefiting from working with their colleagues through sharing of data in their notebooks.  Real time feedback directly in electronic notebooks from faculty and TAs enhances learning.