BMPs, the largest family of secreted signaling molecules within the TGF-beta super-family, regulate many processes critical for organismal development, as well as tissue repair. Many components of the TGF-a and BMP signaling pathways are directly implicated in a number of human diseases, most notably heritable neoplastic vascular disorders and gastrointestinal neoplasias. As morphogens, many BMPs are capable of eliciting diverse cellular responses, thought to be determined by the level of signaling. Interestingly, several human disorders and syndromes have recently been attributed to abnormal levels of signaling by BMPs or TGF-betas. In studies of development, the morphogen gradient theory has been useful in guiding research aimed at understanding how positional information and the specification of multiple cell fates are achieved. Despite our extensive knowledge of which molecules are important in patterning, such as BMPs, our understanding of how gradients of morphogenetic information are generated and interpreted is surprisingly limited. Data from our laboratory shows that the BMP activity gradient responsible for patterning the Drosophila wing is generated by the differential contribution of two BMPs, Gbb and Dpp. Dpp exhibits short range signaling activity to pattern cell fates near its source in the central domain of the wing imaginal disc, while Gbb exhibits long range signaling activity to pattern elements found far from its source. The experiments outlined in this proposal are aimed at identifying the molecular basis of this difference in range of signaling.
Our aims are:
Aim 1 : Identify the protein domains of BMP ligands important in determining functional range;
Aim 2 : Identify sequences and processes critical for regulating functional range;
and Aim 3 : Elucidate the relationship between physical range and functional range. The unique strength of the proposed structure/function analysis is that function will be assayed in vivo, at endogenous levels, in the normal context of the developing organ. Such an analysis is essential for furthering our understanding of BMP signaling, given the extreme sensitivity of cells to the level of signaling output from this pathway. The role of the BMP type I receptors in generating the BMP activity gradient will be determined, as will the effect of BMP ligand co-expression. Results from these experiments will have a significant impact on our understanding of how BMP signaling levels are regulated.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM068118-03
Application #
7173242
Study Section
Development - 1 Study Section (DEV)
Program Officer
Haynes, Susan R
Project Start
2005-02-01
Project End
2009-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
3
Fiscal Year
2007
Total Cost
$279,350
Indirect Cost
Name
Brown University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
Borensztejn, Antoine; Mascaro, Alexandra; Wharton, Kristi A (2018) JAK/STAT signaling prevents excessive apoptosis to ensure maintenance of the interfollicular stalk critical for Drosophila oogenesis. Dev Biol 438:1-9
Borensztejn, Antoine; Mascaro, Alexandra; Wharton, Kristi A (2018) Corrigendum to ""JAK/STAT signaling prevents excessive apoptosis to ensure maintenance of the interfollicular stalk critical for Drosophila oogenesis"" [Dev. Biol. 438 (2018) 1-9]. Dev Biol 444:41
?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
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
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
Wharton, Kristi A; Serpe, Mihaela (2013) Fine-tuned shuttles for bone morphogenetic proteins. Curr Opin Genet Dev 23:374-84
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
Akiyama, Takuya; Marqu├ęs, Guillermo; Wharton, Kristi A (2012) A large bioactive BMP ligand with distinct signaling properties is produced by alternative proconvertase processing. Sci Signal 5:ra28
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
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

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