signaling directs the development of multiple organs and tissues in embryogenesis, and is the causative factor in multiple congenital and adult diseases. Numerous studies suggest the potential for modulating BMP signaling in the treatment of disorders as diverse as kidney disease, pulmonary hypertension, and in medical applications such as orthopedics, endodontics, and tissue engineering. BMP heterodimers are receiving increasing attention recently due to their higher signaling activity to BMP homodimers and their potential in therapeutics. To understand how BMP signaling can generate diverse cellular responses in a myriad of biological contexts and affect disease, as well as how BMP heterodimers can be most effectively used in therapeutics, it is imperative to understand the mechanism by which BMPs signal. A key function of BMP signaling in vertebrate development is to pattern the cells along the dorsoventral (DV) embryonic axis during late blastula and gastrula stages. BMP signaling activity is thought to act as a morphogen, specifying distinct cell types at different activity levels. Dorsally-emanating BMP antagonists are important in generating the gradient of BMP activity with low levels dorsally and highest levels ventrally. In the previous grant period, BMP heterodimers were found to exclusively signal in zebrafish DV patterning, providing an in vivo, physiological assay in vertebrates for BMP heterodimer signaling. The studies here will use this unique in vivo animal model setting to elucidate the mechanism that leads to the exclusive signaling by BMP heterodimers in zebrafish DV patterning. The results are expected to be broadly relevant to BMP heterodimer signaling mechanisms in other biological contexts. A poorly understood mechanism restricts BMP antagonists to dorsal regions during late blastula stages. A new genetic regulator of this process in zebrafish was identified in the past grant period, which when deficient leads to the ventral expansion of BMP antagonists and dorsal midline mesoderm causing the dramatic formation of multiple dorsal axes. The mutant gene encodes the integrator complex subunit 6 (ints6), representing the first loss-of-function mutation of this gene to be studied in any organism. These studies will be extended here to determine how Ints6 functions with the other maternal regulators of DV patterning to elucidate its mechanism of action. Lastly, the molecular nature and role played by a new maternal-effect mutant gene with a defect similar to ints6 will be studied. It is postulated to encode a novel gene or an already known gene with a new function in DV patterning, which will allow the elaboration of the molecular mechanisms mediating vertebrate DV patterning. !

Public Health Relevance

The Bone Morphogenetic Protein (BMP) and TGF? family of secreted signaling molecules directs the development of multiple organs and tissue types and is implicated in congenital and adult diseases. Ongoing investigations suggest the potential for modulating BMP and TGF? signaling in the treatment of disorders as diverse as kidney disease, pulmonary hypertension, pancreatic, colorectal, and other cancers, and in medical applications such as orthopedics, endodontics, bone regeneration, and tissue engineering. To understand how BMP signaling can generate diverse cellular responses in a myriad of biological contexts and affect disease, it is imperative to understand the mechanism by which BMPs signal and how these signals are regulated in tissue development, as will be studied here.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM056326-14
Application #
8372690
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Hoodbhoy, Tanya
Project Start
1997-08-01
Project End
2016-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
14
Fiscal Year
2012
Total Cost
$376,373
Indirect Cost
$136,373
Name
University of Pennsylvania
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Ge, Xiaoyan; Grotjahn, Danielle; Welch, Elaine et al. (2014) Hecate/Grip2a acts to reorganize the cytoskeleton in the symmetry-breaking event of embryonic axis induction. PLoS Genet 10:e1004422
Kapp, Lee D; Abrams, Elliott W; Marlow, Florence L et al. (2013) The integrator complex subunit 6 (Ints6) confines the dorsal organizer in vertebrate embryogenesis. PLoS Genet 9:e1003822
Hashiguchi, Megumi; Mullins, Mary C (2013) Anteroposterior and dorsoventral patterning are coordinated by an identical patterning clock. Development 140:1970-80
Langdon, Yvette G; Mullins, Mary C (2011) Maternal and zygotic control of zebrafish dorsoventral axial patterning. Annu Rev Genet 45:357-77
Dutko, James A; Mullins, Mary C (2011) SnapShot: BMP signaling in development. Cell 145:636, 636.e1-2
Kaplan, Frederick S; Seemann, Petra; Haupt, Julia et al. (2010) Investigations of activated ACVR1/ALK2, a bone morphogenetic protein type I receptor, that causes fibrodysplasia ossificans progressiva. Methods Enzymol 484:357-73
Shen, Qi; Little, Shawn C; Xu, Meiqi et al. (2009) The fibrodysplasia ossificans progressiva R206H ACVR1 mutation activates BMP-independent chondrogenesis and zebrafish embryo ventralization. J Clin Invest 119:3462-72
Little, Shawn C; Mullins, Mary C (2006) Extracellular modulation of BMP activity in patterning the dorsoventral axis. Birth Defects Res C Embryo Today 78:224-42
Connors, Stephanie A; Tucker, Jennifer A; Mullins, Mary C (2006) Temporal and spatial action of tolloid (mini fin) and chordin to pattern tail tissues. Dev Biol 293:191-202
Little, Shawn C; Mullins, Mary C (2004) Twisted gastrulation promotes BMP signaling in zebrafish dorsal-ventral axial patterning. Development 131:5825-35

Showing the most recent 10 out of 20 publications