Craniofacial development is a uniquely complex morphogenetic process in vertebrate ontogeny, creating evolutionary plasticity but also developmental vulnerability. The head and face are derived from many tissue precursors, which require a precise orchestration of pattern formation, cell migration, proliferation, apoptosis, and inductive interactions to achieve a functional end. Many of these events are mediated by secreted cytokines, whose activity must be precisely regulated to preclude inappropriate cellular responses. Bone Morphogenetic Proteins (BMPs) are a family of secreted ligands which have potent effects on many aspects of craniofacial development, particularly the closely related proteins BMP2 and BMP4. Their activity is thought to be important in the growth or patterning of such diverse tissues as the brain, the skull, the pituitary gland, the teeth, and the precursors of the face. Research from Drosophila and Xenopus indicate that BMP2/4 signal transduction is regulated in large part by antagonistic proteins such as Chordin (Chd) and Noggin (Nog). In frogs, Chd and Nog promote anterior development, and Chd is essential for normal head development in zebrafish. Preliminary work described in this proposal shows that these genes are required for development of the mammalian head. Lack of Chd in an inbred genetic background results in a group of craniofacial skeletal and soft-tissue defects involving neural crest derivatives, similar to those seen in certain human syndromes. Chd and Nog together are required early for head development, but are also involved specifically in development of the forebrain, mouth, nose, mandible, numerous bones of the skull, and other craniofacial tissues. The major aims of this proposal are: 1) to characterize the spatiotemporal expression patterns of Chd and Nog to clarify their roles in craniofacial development; 2) to determine the critical sites and times of action for Chd and Nog in head induction using embryonic stem cell chimeras and tissue recombinants; 3) to determine the functions of these genes in growth and patterning of craniofacial tissues; and 4) to assess whether ectopic BMP signaling reproduces the craniofacial defects of the mutants.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE013674-05
Application #
6855768
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Program Officer
Small, Rochelle K
Project Start
2001-04-01
Project End
2006-11-30
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
5
Fiscal Year
2005
Total Cost
$384,228
Indirect Cost
Name
Duke University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Matsui, Maiko; Klingensmith, John (2014) Multiple tissue-specific requirements for the BMP antagonist Noggin in development of the mammalian craniofacial skeleton. Dev Biol 392:168-81
Stottmann, Rolf W; Klingensmith, John (2011) Bone morphogenetic protein signaling is required in the dorsal neural folds before neurulation for the induction of spinal neural crest cells and dorsal neurons. Dev Dyn 240:755-65
Yang, Yu-Ping; Anderson, Ryan M; Klingensmith, John (2010) BMP antagonism protects Nodal signaling in the gastrula to promote the tissue interactions underlying mammalian forebrain and craniofacial patterning. Hum Mol Genet 19:3030-42
Klingensmith, John; Matsui, Maiko; Yang, Yu-Ping et al. (2010) Roles of bone morphogenetic protein signaling and its antagonism in holoprosencephaly. Am J Med Genet C Semin Med Genet 154C:43-51
Choi, Murim; Klingensmith, John (2009) Chordin is a modifier of tbx1 for the craniofacial malformations of 22q11 deletion syndrome phenotypes in mouse. PLoS Genet 5:e1000395
Ahuja, Rashmi; Pinyol, Roser; Reichenbach, Nicole et al. (2007) Cordon-bleu is an actin nucleation factor and controls neuronal morphology. Cell 131:337-50
Ilagan, Roger; Abu-Issa, Radwan; Brown, Doris et al. (2006) Fgf8 is required for anterior heart field development. Development 133:2435-45
Miura, Shigeto; Davis, Shannon; Klingensmith, John et al. (2006) BMP signaling in the epiblast is required for proper recruitment of the prospective paraxial mesoderm and development of the somites. Development 133:3767-75
Stottmann, Rolf W; Berrong, Mark; Matta, Karen et al. (2006) The BMP antagonist Noggin promotes cranial and spinal neurulation by distinct mechanisms. Dev Biol 295:647-63
Anderson, Ryan M; Stottmann, Rolf W; Choi, Murim et al. (2006) Endogenous bone morphogenetic protein antagonists regulate mammalian neural crest generation and survival. Dev Dyn 235:2507-20

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