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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM056211-14A1
Application #
8216232
Study Section
Special Emphasis Panel (ZRG1-CB-Z (02))
Program Officer
Hoodbhoy, Tanya
Project Start
1997-09-01
Project End
2015-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
14
Fiscal Year
2012
Total Cost
$373,490
Indirect Cost
$152,490
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
Pauli, Andrea; Norris, Megan L; Valen, Eivind et al. (2014) Toddler: an embryonic signal that promotes cell movement via Apelin receptors. Science 343:1248636
Gagnon, James A; Valen, Eivind; Thyme, Summer B et al. (2014) Efficient mutagenesis by Cas9 protein-mediated oligonucleotide insertion and large-scale assessment of single-guide RNAs. PLoS One 9:e98186
Zhang, Yong; Vastenhouw, Nadine L; Feng, Jianxing et al. (2014) Canonical nucleosome organization at promoters forms during genome activation. Genome Res 24:260-6
Chew, Guo-Liang; Pauli, Andrea; Rinn, John L et al. (2013) Ribosome profiling reveals resemblance between long non-coding RNAs and 5' leaders of coding RNAs. Development 140:2828-34
Müller, Patrick; Rogers, Katherine W; Jordan, Ben M et al. (2012) Differential diffusivity of Nodal and Lefty underlies a reaction-diffusion patterning system. Science 336:721-4
Vastenhouw, Nadine L; Schier, Alexander F (2012) Bivalent histone modifications in early embryogenesis. Curr Opin Cell Biol 24:374-86
Pauli, Andrea; Valen, Eivind; Lin, Michael F et al. (2012) Systematic identification of long noncoding RNAs expressed during zebrafish embryogenesis. Genome Res 22:577-91
Muller, Patrick; Schier, Alexander F (2011) Extracellular movement of signaling molecules. Dev Cell 21:145-58
Vastenhouw, Nadine L; Zhang, Yong; Woods, Ian G et al. (2010) Chromatin signature of embryonic pluripotency is established during genome activation. Nature 464:922-6
Woods, Ian G; Schier, Alexander F (2008) Targeted mutagenesis in zebrafish. Nat Biotechnol 26:650-1

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