The long-range goal of the proposed studies is to identify the mechanisms of cell fate specification during vertebrate development. The focus is on the Nodal TGFss pathway, which plays fundamental roles in mesoderm and endoderm induction and left-right axis determination. Nodal signaling has concentration-dependent effects on the formation of mesodermal and endodermal cell types, but it is unclear how graded Nodal signaling induces different fates. To gain a deeper understanding of Nodal signaling, this project will determine (1) how ligand diffusion and clearance contribute to the distribution of Nodal signals, and (2) how graded Nodal signaling is interpreted in responding cells. These studies will be performed in zebrafish embryos, because sophisticated live imaging can be combined with genetic approaches. The proposed studies will advance the understanding of Nodal signaling and provide general insights into how graded signals pattern fields of cells. Abnormalities in human Nodal signaling are associated with forebrain anomalies, left-right defects and cancer. The proposed studies will thus help to provide the necessary context for understanding human birth defects and disease. Nodal signaling is also employed to maintain and differentiate human embryonic stem cells. The proposed studies will thus help to inform strategies to manipulate stem cells for tissue repair and disease modeling. )

Public Health Relevance

This project addresses how the myriad of different cell types form during animal development. Abnormal regulation of this process leads to birth defects and cancer, whereas methodical manipulation of this process can help understand and treat degenerative diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CB-Z (02))
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Hoodbhoy, Tanya
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Harvard University
Schools of Arts and Sciences
United States
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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:
Li-Villarreal, Nanbing; Forbes, Meredyth M; Loza, Andrew J et al. (2016) Dachsous1b cadherin regulates actin and microtubule cytoskeleton during early zebrafish embryogenesis. Development 143:1832
Xu, Han; Xu, Kexin; He, Housheng H et al. (2016) Integrative Analysis Reveals the Transcriptional Collaboration between EZH2 and E2F1 in the Regulation of Cancer-Related Gene Expression. Mol Cancer Res 14:163-172
Thyme, Summer B; Akhmetova, Laila; Montague, Tessa G et al. (2016) Internal guide RNA interactions interfere with Cas9-mediated cleavage. Nat Commun 7:11750
McKenna, Aaron; Findlay, Gregory M; Gagnon, James A et al. (2016) Whole-organism lineage tracing by combinatorial and cumulative genome editing. Science 353:aaf7907
Thyme, Summer B; Schier, Alexander F (2016) Polq-Mediated End Joining Is Essential for Surviving DNA Double-Strand Breaks during Early Zebrafish Development. Cell Rep 15:707-714

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