The long-range goal of the proposed studies is to identify mechanisms of cell fate specification and movement during vertebrate development. The focus is on the Nodal TGF pathway, which plays fundamental roles in mesendoderm specification and left-right axis determination, and the Toddler GPCR signaling pathway, which is essential for normal internalization of mesendoderm during gastrulation. The essential functions of Nodal and Toddler signaling are firmly established but the mechanisms by which they exert their roles are largely elusive to gain a deeper understanding of Nodal morphogen signaling, this project will determine how feedback inhibition regulates mesendoderm formation and how graded Nodal signaling is interpreted in responding cells. To reveal the cellular and molecular roles of Toddler signaling, this project will determine how Toddler signaling regulates the movement and adhesion of cells. These studies will be performed in zebrafish embryos, because sophisticated live imaging can be combined with genetic and genomic approaches. The proposed studies will provide general insights into how signals pattern fields of cells and control the movement of cells. Since Nodal and Toddler signaling are conserved in humans, the proposed studies will also provide the context necessary to understand birth defects, cancer and other diseases and to inform strategies to program cells to form specific cell types and tissues for disease-modeling and regeneration.

Public Health Relevance

This project addresses how the myriad of different cell types form during early animal development. This project will help understand how birth defects and cancer arise and how cells can be programmed to form specific cell types and tissues.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM056211-19
Application #
9198872
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Hoodbhoy, Tanya
Project Start
1997-09-01
Project End
2020-12-31
Budget Start
2017-01-01
Budget End
2017-12-31
Support Year
19
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138
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Norris, Megan L; Pauli, Andrea; Gagnon, James A et al. (2017) Toddler signaling regulates mesodermal cell migration downstream of Nodal signaling. Elife 6:
Montague, Tessa G; Schier, Alexander F (2017) Vg1-Nodal heterodimers are the endogenous inducers of mesendoderm. Elife 6:
Rogers, Katherine W; Lord, Nathan D; Gagnon, James A et al. (2017) Nodal patterning without Lefty inhibitory feedback is functional but fragile. Elife 6:
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