The neural crest is a multipotent embryonic cell population that plays a central role in craniofacial development, giving rise to most of the skeletal elements of the face. Abnormal neural crest development is the leading cause of craniofacial malformations and birth defects. Specification of the cranial neural crest is a complex process that requires interplay between signaling molecules, receptors, and transcriptional regulators. In particular, the Wnt signaling pathway has been shown to be a major driver of neural crest development. Data obtained from different model organisms show that inhibition of Wnt activity abrogates expression of neural crest genes, while overactivation of canonical Wnt pathway components results in expansion of neural crest fates. However, the molecular mechanism through which Wnt signaling elicits neural crest identity remains elusive. In this application, I will investigate how the Wnt-pathway drives activation of the genes that endow the neural crest with its unique features. I hypothesize that Wnt-effector genes cooperate with transcriptional regulators present in progenitors to trigger the neural crest specification program. This hypothesis is supported by my preliminary experiments, which suggests that transcriptional regulator Axud1 acts as a previously unidentified link between Wnt signaling and neural crest specification. Here, I will determine the role of Axud1 in specification by using loss of function approaches in the chicken embryo, and scrutinize how it is activated by Wnts in neural crest progenitors. Subsequently, I will investigate how members of the Wnt pathway interact with other drivers of neural crest specification to activate the expression of downstream targets at the cis-regulatory level. The results of the proposed experiments will shed light on how signaling pathways are integrated with the transcriptional machinery to allow for the emergence of nascent neural crest cells. Expanding the knowledge of molecular programs controlling the development of the cephalic neural crest will yield novel insights into the genetic basis of craniofacial disease and can impact therapeutic and regenerative applications.

Public Health Relevance

The neural crest gives rise to most of the skeletal elements of the face and is thus implicated in many congenital birth defects. Expanding our understanding of molecular mechanisms controlling cranial neural crest development will yield novel insights into the genetic basis of craniofacial disease. This may inform upon diagnosis, therapeutic intervention and also yield approaches guiding directed differentiation of stem cells for the purpose of repair and regeneration. !

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Career Transition Award (K99)
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NIDR Special Grants Review Committee (DSR)
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Frieden, Leslie A
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California Institute of Technology
Schools of Arts and Sciences
United States
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Simoes-Costa, Marcos; Bronner, Marianne E (2016) Reprogramming of avian neural crest axial identity and cell fate. Science 352:1570-3
Bronner, Marianne E; Simões-Costa, Marcos (2016) The Neural Crest Migrating into the Twenty-First Century. Curr Top Dev Biol 116:115-34
Simões-Costa, Marcos; Bronner, Marianne E (2015) Establishing neural crest identity: a gene regulatory recipe. Development 142:242-57
Simões-Costa, Marcos; Stone, Michael; Bronner, Marianne E (2015) Axud1 Integrates Wnt Signaling and Transcriptional Inputs to Drive Neural Crest Formation. Dev Cell 34:544-54
Green, Stephen A; Simoes-Costa, Marcos; Bronner, Marianne E (2015) Evolution of vertebrates as viewed from the crest. Nature 520:474-482
Hu, Na; Strobl-Mazzulla, Pablo H; Simoes-Costa, Marcos et al. (2014) DNA methyltransferase 3B regulates duration of neural crest production via repression of Sox10. Proc Natl Acad Sci U S A 111:17911-6