mesenchyme cells of the sea urchin embryo provide a model system for exploring details of an epithelial to mesenchyme transition (EMT). This morphogenetic movement occurs in all organisms that produce, muscle, bone, and other mesenchyme tissues. Curiously, many parts of the EMT process are co-opted and used by metastatic cells often leading to catastrophic consequences. The EMT is highly complex and normally thought to be well controlled. Here, the system will be examined in detail to determine how the EMT is transcriptionally controlled and coordinated under normal circumstances. A developmental Gene Regulatory Network (GRN) was assembled during the previous funding cycles, and 10 transcription factors were discovered to have the proximal responsibility of controlling the EMT. Different subsets of the 10 transcription factors separately control onset of motility, invasive penetration of the basal lamina, de-adhesion, endocytosis, and other components of the EMT. This project will obtain answers to missing information on how the control circuit is activated, how the 10 transcription factors are integrated to coordinately regulate the complex cellular sequence that occurs in an EMT, and how the same control circuit is activated at least twice in development by two different tissues. The project will examine how 12 different cellular events are coordinately timed to sequence the transition. Each function utilizes many proteins and these must fall under the overall control circuitry. Since the same controlling circuit is activated in different cell types just upstream of EMT onset, the discovery f how that cell switches into the EMT circuit will be of great value both in normal embryonic cells, and in various disease states where an EMT launches the dissemination of abnormal cells.

Public Health Relevance

An epithelial-mesenchymal transition (EMT) is one of the first steps in metastasis of all carcinomas, and it is a necessary step in the formation of normal mesenchyme tissues. Studies have shown that much of the biology of the metastatic EMT has been co-opted from the normal EMT sequence. The goal of this project is to assemble the transcriptional circuitry that regulates the normal progression of an EMT in a model organism to understand how this process is controlled at a molecular level.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD014483-31A1
Application #
8433052
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Mukhopadhyay, Mahua
Project Start
1980-07-01
Project End
2018-05-31
Budget Start
2013-09-05
Budget End
2014-05-31
Support Year
31
Fiscal Year
2013
Total Cost
$180,420
Indirect Cost
$63,991
Name
Duke University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Saunders, Lindsay R; McClay, David R (2014) Sub-circuits of a gene regulatory network control a developmental epithelial-mesenchymal transition. Development 141:1503-13
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Croce, Jenifer; Range, Ryan; Wu, Shu-Yu et al. (2011) Wnt6 activates endoderm in the sea urchin gene regulatory network. Development 138:3297-306
Croce, Jenifer C; McClay, David R (2010) Dynamics of Delta/Notch signaling on endomesoderm segregation in the sea urchin embryo. Development 137:83-91

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