Our long term goal is to understand how members of the TGF? superfamily act to exert a wide range of cell- type specific actions during development. Our current focus is on the role of TGF? ligands and their primary signal transducers, the Smads, in two sets of developmental events: 1) the regulation of migration of cell populations that establish the craniofacial skeleton and the body wall musculature;2) the normal growth of the tail and the regeneration of this structure following surgical extirpation. Migration of cell populations over extended distances in the embryo prior to their terminal differentiation is a critical component of the establishment of embryonic pattern. These migrations involve cell behaviors and regulatory programs which may be recapitulated during tumor metastasis, making an understanding of their regulation important for tumor biology as well as embryology. The craniofacial skeleton is made up primarily of neural crest cells that migrate from the edge of the anterior neural plate into the craniofacial region, where they differentiate into cartilage and bone. The muscle of the body wall is made up of muscle precursor cells that migrate from the somites to the ventro-lateral body wall, where they differentiate into muscle. In each case, preliminary work implicates BMP signals as regulators of the cell migration and/or the subsequent differentiation of the migratory cell. We will use a novel conditional inhibitor developed in our lab to understand how BMPs regulate these processes. The Xenopus tail has been shown to be a powerful system for studying the molecular basis of complex regenerative events. We have identified a TGF? superfamily ligand, GDF11, that controls outgrowth of the normal tail through the activation of Smad2. We plan to explore how GDF11 and Smad2 activation during tail regeneration interacts with other signaling pathways to establish the regenerative program. Understanding how extracellular factors control cell and tissue migration during normal development, during regenerative healing following extensive tissue damage, and during pathological processes such as tumor metastasis, provides a basis for new paths to therapeutic regulation of these events. The study of TGF? superfamily ligands provides a common approach, and a common set of molecular tools, with which to understand the regulation of these important physiological processes.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD029468-16
Application #
7599558
Study Section
Development - 1 Study Section (DEV)
Program Officer
Mukhopadhyay, Mahua
Project Start
1992-08-05
Project End
2011-02-28
Budget Start
2009-03-01
Budget End
2010-02-28
Support Year
16
Fiscal Year
2009
Total Cost
$424,795
Indirect Cost
Name
Harvard University
Department
Dentistry
Type
Schools of Dentistry
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Ho, Diana M; Yeo, Chang-Yeol; Whitman, Malcolm (2010) The role and regulation of GDF11 in Smad2 activation during tailbud formation in the Xenopus embryo. Mech Dev 127:485-95
Danciu, Theodora E; Whitman, Malcolm (2010) Oxidative stress drives disulfide bond formation between basic helix-loop-helix transcription factors. J Cell Biochem 109:417-24
Ho, Diana M; Whitman, Malcolm (2008) TGF-beta signaling is required for multiple processes during Xenopus tail regeneration. Dev Biol 315:203-16
Anderson, Sarah B; Goldberg, Alfred L; Whitman, Malcolm (2008) Identification of a novel pool of extracellular pro-myostatin in skeletal muscle. J Biol Chem 283:7027-35
Lee, Kyu-Ho; Evans, Samuel; Ruan, Todd Y et al. (2004) SMAD-mediated modulation of YY1 activity regulates the BMP response and cardiac-specific expression of a GATA4/5/6-dependent chick Nkx2.5 enhancer. Development 131:4709-23
Faure, Sandrine; de Santa Barbara, Pascal; Roberts, Drucilla J et al. (2002) Endogenous patterns of BMP signaling during early chick development. Dev Biol 244:44-65
Whitman, M; Mercola, M (2001) TGF-beta superfamily signaling and left-right asymmetry. Sci STKE 2001:re1