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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Method to Extend Research in Time (MERIT) Award (R37)
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Development - 2 Study Section (DEV2)
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Hoodbhoy, Tanya
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Harvard University
Schools of Arts and Sciences
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Almuedo-Castillo, María; Bläßle, Alexander; Mörsdorf, David et al. (2018) Scale-invariant patterning by size-dependent inhibition of Nodal signalling. Nat Cell Biol 20:1032-1042
Freyer, Laina; Hsu, Chih-Wei; Nowotschin, Sonja et al. (2017) Loss of Apela Peptide in Mice Causes Low Penetrance Embryonic Lethality and Defects in Early Mesodermal Derivatives. Cell Rep 20:2116-2130
Rogers, Katherine W; Lord, Nathan D; Gagnon, James A et al. (2017) Nodal patterning without Lefty inhibitory feedback is functional but fragile. Elife 6:
Montague, Tessa G; Schier, Alexander F (2017) Vg1-Nodal heterodimers are the endogenous inducers of mesendoderm. Elife 6:
Norris, Megan L; Pauli, Andrea; Gagnon, James A et al. (2017) Toddler signaling regulates mesodermal cell migration downstream of Nodal signaling. Elife 6:
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