Bone morphogenetic proteins (BMPs) are members of the TGF? superfamily of secreted signaling molecules. BMP signaling is an ancient pathway and can even be found in members of the phylum Porifera (sponges). The roles of BMPs have diverged in evolution and include the control of gametogenesis, early embryonic development, cell differentiation/apoptosis, and tissue homeostasis in the adult. Great progress has been made on the mechanisms controlling BMP signaling from the ligands in the extracellular environment, through their receptors and into the nucleus. This knowledge has led to the concept of a "core" pathway that mediates BMP signal transduction to control target gene expression. However, we still know relatively little regarding how this core pathway elicits different responses in different cell types and at different times during development. One reason for this lack of knowledge is that we have not, until recently, had methods to examine how BMPs directly impact genes on a genome-wide level. A second reason is that while we have gained insights into how the intracellular BMP mediators, the Smads, recognize their gene targets, it seems that targeting of genes by the Smads also requires interactions with other transcription factors. It is presently unclear whether these partner proteins function on a gene-by-gene basis or have more broad functions to control whole networks of BMP response genes. We have recently provided evidence that the evolutionarily conserved orthologs of the Drosophila gene schnurri encode a common partner that may be used more widely to promote BMP target gene recognition. Our hypotheses and models are based on the following critical recent findings: 1. we have identified a core BMP-responsive element (BRE) that responds specifically to BMP signaling from Drosophila to Xenopus, zebrafish and mouse. 2. BRE reporter gene experiments in Xenopus reveal that BMP signaling is not only active in the mesoderm and ectoderm, as is well known, but also in the endoderm 3. Affymetrix gene chips suggest that endodermal BMP signaling activates a core gene network also induced in the other two germ layers 4. We have identified a critical phylogenetically-conserved transcription factor (Schnurri- related zinc finger protein) mediating BMP signaling through the BRE We propose to address the following specific aims: 1. Role(s) of BMP signaling in endodermal gene regulatory networks 2. Schnurri-mediated BMP signaling during embryogenesis 3. Elucidation of a BMP signaling network

Public Health Relevance

While study of the molecular mechanisms governing BMP signaling remains a major focus of developmental biology, we still have a very limited understanding of how BMPs achieve their biological effects, particularly at the level of transcription factors mediated target gene activation, and how the target genes function. Because BMP signaling is a highly conserved and widely- used developmental signaling systems in animal evolution, uncovering the gene regulatory mechanisms governing these processes has broad impact. Additionally, mutations in genes regulating BMP signaling cause various diseases (e.g., juvenile polyposis syndrome, primary pulmonary hypertension, Cowden's syndrome) and developmental abnormalities. Identification of candidate genes and signaling components will aid in developing new diagnosis and treatments.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD056219-04
Application #
8242087
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Mukhopadhyay, Mahua
Project Start
2009-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$286,475
Indirect Cost
$89,267
Name
University of California Irvine
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Zheng, Zhenzhen; Christley, Scott; Chiu, William T et al. (2014) Inference of the Xenopus tropicalis embryonic regulatory network and spatial gene expression patterns. BMC Syst Biol 8:3
Alexander, Courtney; Zuniga, Elizabeth; Blitz, Ira L et al. (2011) Combinatorial roles for BMPs and Endothelin 1 in patterning the dorsal-ventral axis of the craniofacial skeleton. Development 138:5135-46
Onai, Takayuki; Yu, Jr-Kai; Blitz, Ira L et al. (2010) Opposing Nodal/Vg1 and BMP signals mediate axial patterning in embryos of the basal chordate amphioxus. Dev Biol 344:377-89