Sox proteins fall into a large class of transcription factors related to SRY, the testis determining factor. Expression of these proteins in defined cell types during embryogenesis appears to govern cell fate decisions. One member of this family, mouse Sox9, has been shown to regulate cartilage formation by binding and activating the chondrocyte specific enhancer of type II collagen (Col2a1). Consistent with this role, Col2a1 and Sox9 are coexpressed in all chondrogenic precursors. Mutations in Sox9 result in Campomelic Dysplasia (CD), a lethal human disorder characterized by XY sex reversal and severe skeletal malformations. During embryogenesis, Sox 9 is also expressed in neural crest progenitors. CD patients also present defects in craniofacial skeletal elements of neural crest origin (palate and jaws) suggesting that Sox9 may play an important role in cranial neural crest formation. Preliminary studies indicate that Sox9 is required for neural crest formation during Xenopus laevis development. Sox9 is expressed at the gastrula stage in the neural crest-forming region. In this tissue, Sox9 colocalizes spatially and temporally with Slug, known to be the earliest gene activated in response to neural crest-inducing signals. Depletion of Sox9 in developing embryos, using a novel antisense approach, causes a loss of neural crest progenitors and an expansion of neural tissues. Later during embryogenesis, antisense-treated embryos have a specific loss or reduction of neural crest-derived skeletal elements, mimicking aspect of the craniofacial defects observed in CD patients. Our hypothesis is that the transcription factor Sox9 is an essential component of the signaling cascade leading to neural crest formation. We propose: 1)- To characterize Sox9 activity within the neural crest by defining the timing of Sox9 requirement for neural crest formation. 2)- To determine whether Sox9 activity is required for specific neural crest lineages, by targeting Sox9 depletion in areas of the neural fold fated to form either cranial or trunk crest derivatives. 3)- To define the origin and the nature of the signals regulating Sox9 expression in the neural folds. The spectrum of abnormalities in CD patients indicates a fundamental role of Sox9 in sex determination and skeletal development but also important roles in other developmental processes. The work proposed here will address the function of Sox9 in the signaling cascade leading to neural crest formation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE014212-04
Application #
6845394
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Small, Rochelle K
Project Start
2002-04-01
Project End
2007-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
4
Fiscal Year
2005
Total Cost
$277,375
Indirect Cost
Name
University of Pennsylvania
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Bae, Chang-Joon; Hong, Chang-Soo; Saint-Jeannet, Jean-Pierre (2018) Anosmin-1 is essential for neural crest and cranial placodes formation in Xenopus. Biochem Biophys Res Commun 495:2257-2263
Devotta, Arun; Hong, Chang-Soo; Saint-Jeannet, Jean-Pierre (2018) Dkk2 promotes neural crest specification by activating Wnt/?-catenin signaling in a GSK3? independent manner. Elife 7:
Hong, Chang-Soo; Saint-Jeannet, Jean-Pierre (2017) Znf703, a novel target of Pax3 and Zic1, regulates hindbrain and neural crest development in Xenopus. Genesis 55:
Devotta, Arun; Juraver-Geslin, Hugo; Gonzalez, Jose Antonio et al. (2016) Sf3b4-depleted Xenopus embryos: A model to study the pathogenesis of craniofacial defects in Nager syndrome. Dev Biol 415:371-382
Jaurena, Maria Belen; Juraver-Geslin, Hugo; Devotta, Arun et al. (2015) Zic1 controls placode progenitor formation non-cell autonomously by regulating retinoic acid production and transport. Nat Commun 6:7476
Bae, Chang-Joon; Jeong, Juhee; Saint-Jeannet, Jean-Pierre (2015) A novel function for Egr4 in posterior hindbrain development. Sci Rep 5:7750
Hong, Chang-Soo; Devotta, Arun; Lee, Young-Hoon et al. (2014) Transcription factor AP2 epsilon (Tfap2e) regulates neural crest specification in Xenopus. Dev Neurobiol 74:894-906
Bae, Chang-Joon; Park, Byung-Yong; Lee, Young-Hoon et al. (2014) Identification of Pax3 and Zic1 targets in the developing neural crest. Dev Biol 386:473-83
Saint-Jeannet, Jean-Pierre; Moody, Sally A (2014) Establishing the pre-placodal region and breaking it into placodes with distinct identities. Dev Biol 389:13-27
Lee, Young-Hoon; Williams, Allison; Hong, Chang-Soo et al. (2013) Early development of the thymus in Xenopus laevis. Dev Dyn 242:164-78

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