This proposal concerns molecular mechanisms leading to the development of neural crest cells. The neural crest is a population of stem-cell-like cells, which form in vertebrate embryos at the neural plate border and migrate to diverse locations in the body to give rise to diverse cell types, including face cartilage, melanocytes and the peripheral nervous system. Neural crest forms as a result of inductive interactions of neuroectoderm, epidermal ectoderm and the underlying mesoderm. One embryonic signaling pathway that plays an essential role in neural crest induction is the Wnt pathway, known to control cell proliferation, fates, cell polarity and motility in many cell types. Whereas the role for the Wnt/2-catenin pathway in neural crest regulation has been established, the functions of 2-catenin-independent Wnt signals in this process remain largely unknown. Our preliminary studies reveal a function for 2-catenin-independent Wnt proteins in neural crest specification. We have also discovered that PAR proteins are involved in the activation of neural crest-specific genes. To connect cell polarization to neural crest specification, we plan to investigate the mechanism, by which PAR proteins influence neural crest fates. The proposed studies will evaluate at which developmental step PAR function is required, whether the response to known neural crest regulators is altered and whether the proper subcellular localization of PAR proteins is critical for this process. Using an unbiased protein interaction screen and the candidate protein approach, we will identify downstream targets of PAR proteins, which contribute to neural crest development. Other studies will determine how upstream signaling pathways regulate PAR localization, levels and activity to specify neural crest fates. These experiments will be carried out in Xenopus embryos, which represent a rapid in vivo system for gene function and allow classical cell biological and biochemical experiments. By connecting PAR and Wnt signaling during the initial stages of craniofacial development, the proposed experiments will contribute to the understanding of both the basic developmental mechanisms and will be relevant to the disease. A large number of human diseases, such as craniosynostosis, Waardenburg and Hirschsprung's syndromes, and cancer, have been associated with neural crest abnormalities. Studying the mechanisms underlying the development of the neural crest cells should provide insights into human diseases associated with stem cell disorders and cancer.

Public Health Relevance

This application concerns molecular mechanisms leading to the development of neural crest cells. Since neural crest abnormalities are known to lead to craniosynostosis, Waardenburg and Hirschsprung's syndromes, and cancer, the proposed studies are highly relevant to human diseases associated with stem cell disorders and tumorigenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040972-12
Application #
8394917
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Morris, Jill A
Project Start
2001-02-01
Project End
2016-02-29
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
12
Fiscal Year
2013
Total Cost
$373,783
Indirect Cost
$153,262
Name
Icahn School of Medicine at Mount Sinai
Department
Biology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Sokol, Sergei Y (2016) Mechanotransduction During Vertebrate Neurulation. Curr Top Dev Biol 117:359-76
Ossipova, Olga; Chu, Chih-Wen; Fillatre, Jonathan et al. (2015) The involvement of PCP proteins in radial cell intercalations during Xenopus embryonic development. Dev Biol 408:316-27
Sokol, Sergei Y (2015) Spatial and temporal aspects of Wnt signaling and planar cell polarity during vertebrate embryonic development. Semin Cell Dev Biol 42:78-85
Ossipova, Olga; Chuykin, Ilya; Chu, Chih-Wen et al. (2015) Vangl2 cooperates with Rab11 and Myosin V to regulate apical constriction during vertebrate gastrulation. Development 142:99-107
Ossipova, Olga; Kim, Kyeongmi; Sokol, Sergei Y (2015) Planar polarization of Vangl2 in the vertebrate neural plate is controlled by Wnt and Myosin II signaling. Biol Open 4:722-30
Kim, Kyeongmi; Ossipova, Olga; Sokol, Sergei Y (2015) Neural crest specification by inhibition of the ROCK/Myosin II pathway. Stem Cells 33:674-85
Itoh, Keiji; Sokol, Sergei Y (2014) Expression cloning of camelid nanobodies specific for Xenopus embryonic antigens. PLoS One 9:e107521
Ossipova, Olga; Kim, Kyeongmi; Lake, Blue B et al. (2014) Role of Rab11 in planar cell polarity and apical constriction during vertebrate neural tube closure. Nat Commun 5:3734
Itoh, Keiji; Ossipova, Olga; Sokol, Sergei Y (2014) GEF-H1 functions in apical constriction and cell intercalations and is essential for vertebrate neural tube closure. J Cell Sci 127:2542-53
Chu, Chih-Wen; Gerstenzang, Emma; Ossipova, Olga et al. (2013) Lulu regulates Shroom-induced apical constriction during neural tube closure. PLoS One 8:e81854

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