The morphogen gradient theory has been a useful framework in guiding studies in developmental biology aimed at understanding how multiple cell identities can be specified by few molecules. Research demonstrating the existence of a gradient of BMP signaling activity and its importance in the specification of different cell fates across the developing Drosophila wing have proven that this system is an ideal one to study the molecular mechanisms regulating BMP signaling. Our previous research uncovered two important features of the BMP gradient system. First, we found that two BMP morphogens, Dpp and Gbb, contribute in distinctly different ways to the activity gradient. Second, Sax, one of two type I receptors mediating morphogen signals has a dual function of both promoting and inhibiting signaling. In this renewal application, we propose a research program to extend our first two new findings with regard to the different behaviors of the BMP signaling molecules, Gbb and Dpp and the novel behavior of the Sax receptor. BMPs have profound functions in development and homeostasis, from early embryonic axis specification to the induction of bone growth. Mutations in various components of the BMP signaling pathway are responsible for multiple diseases and syndromes, including juvenile polyposis, brachydactyly, FOP, HHT2, Loeys-Dietz syndrome and pancreatic carcinomas. Clearly, dysregulation of the BMP signaling pathway has serious ramifications on human health and development. Given their potent effects on cellular physiology, BMP ligands have long been a desired therapeutic agent but with varied success as such. In order to ensure success as therapeutics or in disease intervention, the action of these powerful molecules must be understood in the context of the whole organism. The BMP pathway is highly conserved throughout the animal kingdom, at both the molecular and functional level. This allows us to make use of the Drosophila model system to more quickly investigate not only the factors but also the mechanisms responsible for regulating BMP signaling activity. We have the advantage of examining the interplay between different signaling components at their endogenous concentrations, in their normal location, not possible with such rigor in most other experimental systems. We have been able to identify new components and novel biochemical behaviors that impact BMP function and intend to investigate the mechanistic underpinnings of these new findings. Our results will be extrapolated into the human system and will provide valuable insight into our general understanding of BMP signaling, as well as into the intricacies of morphogen gradients as a fundamental mechanism by which different cells in many different organisms acquire their identity.

Public Health Relevance

Our proposed studies address fundamental questions about how the identities of cells in a developing organism are determined and how they maintain their function through life. Critical for this process is the ability of cells to communicate with one another through intercellular signaling pathways. Our experiments will specifically investigate the cooperative nature of the BMP proteins in cell-cell communication and our results will reveal the underlying mechanisms that regulate the activity of these proteins and their receptors in developing tissues. Dysregulation of the BMP signaling pathway is known to give rise to many human birth defects and diseases, thus our findings will be critical for deciphering the mechanisms gone awry that lead to many cancers, Loeys-Dietz syndrome, Fibrodysplasia Ossificans Progressiva (FOP), hereditary hemorrhagic telangiectasia type 2 (HHT2), and juvenile polyposis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM068118-08
Application #
8723839
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Hoodbhoy, Tanya
Project Start
2005-02-01
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
8
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Brown University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Providence
State
RI
Country
United States
Zip Code
02912
Anderson, Edward N; Wharton, Kristi A (2017) Alternative cleavage of the bone morphogenetic protein (BMP), Gbb, produces ligands with distinct developmental functions and receptor preferences. J Biol Chem 292:19160-19178
?ahin, Asl?; Held, Aaron; Bredvik, Kirsten et al. (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, Rebecca E; Hoover, Kendall M; Bulgari, Dinara et al. (2014) Crimpy enables discrimination of presynaptic and postsynaptic pools of a BMP at the Drosophila neuromuscular junction. Dev Cell 31:586-98
Le, Viet Q; Wharton, Kristi A (2012) Hyperactive BMP signaling induced by ALK2(R206H) requires type II receptor function in a Drosophila model for classic fibrodysplasia ossificans progressiva. Dev Dyn 241:200-14
Boulanger, Ana; Farge, Morgane; Ramanoudjame, Christophe et al. (2012) Drosophila motor neuron retraction during metamorphosis is mediated by inputs from TGF-?/BMP signaling and orphan nuclear receptors. PLoS One 7:e40255
Akiyama, Takuya; Marqués, Guillermo; Wharton, Kristi A (2012) A large bioactive BMP ligand with distinct signaling properties is produced by alternative proconvertase processing. Sci Signal 5:ra28
Ballard, Shannon L; Jarolimova, Jana; Wharton, Kristi A (2010) Gbb/BMP signaling is required to maintain energy homeostasis in Drosophila. Dev Biol 337:375-85
Wharton, Kristi; Derynck, Rik (2009) TGFbeta family signaling: novel insights in development and disease. Development 136:3691-7
Twombly, Vern; Bangi, Erdem; Le, Viet et al. (2009) Functional analysis of saxophone, the Drosophila gene encoding the BMP type I receptor ortholog of human ALK1/ACVRL1 and ACVR1/ALK2. Genetics 183:563-79, 1SI-8SI
Bangi, Erdem; Wharton, Kristi (2006) Dpp and Gbb exhibit different effective ranges in the establishment of the BMP activity gradient critical for Drosophila wing patterning. Dev Biol 295:178-93

Showing the most recent 10 out of 11 publications