The cranial neural crest (CNC) cells are stem/progenitor cells that contribute to the vertebrate craniofacial structures and cardiac tissues One of the earliest and most critical stages in CNC development is the specification of the CNC, which requires induction of the transcription factor Snail2, a process that is also used by carcinoma cells to trigger their invasion. Therefore, understanding the basic mechanisms for CNC specification is critical for developing new methodologies for the prevention and treatment of CNC-related birth defects and carcinoma invasion. The goal of the current application is to elucidate the molecular pathways through which ADAMs 13 and 19, two disintegrin metalloproteinases (ADAMs), function in CNC specification. The application has three specific aims.
The first aim i s to define the roles of ADAM13 in regulating canonical Wnt signaling. The hypothesis to be tested is that ADAM13 cleaves and inactivates two ephrin-Bs, which function as novel antagonists of canonical Wnt signaling, a major signaling pathway that is essential for CNC specification.
The second aim i s to determine the mechanism of action for ADAM19 in CNC specification, and the focus will be on the functional interaction between ADAMs 13 and 19. In the third aim, both candidate and genomic approaches will be used to identify the downstream transcriptional targets of the ADAM-ephrin-Wnt signaling axis. Outcomes of this proposed research should provide new insight into the interactions of ADAM proteases, ephrin-Bs and Wnt signaling, three important regulatory elements in CNC development and carcinoma invasion. Based on this information, new methods may be developed to induce CNC cells for therapeutic purposes or inhibit carcinoma invasion.

Public Health Relevance

Uncontrolled development of progenitor cells that give rise to facial and heart structures may lead to birth defects such as cleft lip and cleft palate as well as heart diseases; similar mechanisms are also involved in cancer cell invasion. This application aims to determine how the early development of these progenitor cells is controlled by a novel cellular pathway, which includes several important genes. The proposed work will provide valuable information that may lead to new methods for prevention and treatment of the related birth defects and cancer invasion.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM114105-06
Application #
9670801
Study Section
Intercellular Interactions Study Section (ICI)
Program Officer
Hoodbhoy, Tanya
Project Start
2015-04-10
Project End
2020-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Delaware
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
059007500
City
Newark
State
DE
Country
United States
Zip Code
19716
Li, Jiejing; Perfetto, Mark; Neuner, Russell et al. (2018) Xenopus ADAM19 regulates Wnt signaling and neural crest specification by stabilizing ADAM13. Development 145:
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Li, Jiejing; Qu, Jiagui; Shi, Yu et al. (2017) Nicotinic acid inhibits glioma invasion by facilitating Snail1 degradation. Sci Rep 7:43173
Bahudhanapati, Harinath; Bhattacharya, Shashwati; Wei, Shuo (2015) Evolution of Vertebrate Adam Genes; Duplication of Testicular Adams from Ancient Adam9/9-like Loci. PLoS One 10:e0136281