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 #
5R01GM056211-15
Application #
8401908
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
2013-01-01
Budget End
2013-12-31
Support Year
15
Fiscal Year
2013
Total Cost
$347,930
Indirect Cost
$134,665
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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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 14:163-72
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; Akhmetova, Laila; Montague, Tessa G et al. (2016) Internal guide RNA interactions interfere with Cas9-mediated cleavage. Nat Commun 7:11750
Chew, Guo-Liang; Pauli, Andrea; Schier, Alexander F (2016) Conservation of uORF repressiveness and sequence features in mouse, human and zebrafish. Nat Commun 7:11663
Dubrulle, Julien; Jordan, Benjamin M; Akhmetova, Laila et al. (2015) Response to Nodal morphogen gradient is determined by the kinetics of target gene induction. Elife 4:
Pauli, Andrea; Montague, Tessa G; Lennox, Kim A et al. (2015) Antisense Oligonucleotide-Mediated Transcript Knockdown in Zebrafish. PLoS One 10:e0139504
Pauli, Andrea; Valen, Eivind; Schier, Alexander F (2015) Identifying (non-)coding RNAs and small peptides: challenges and opportunities. Bioessays 37:103-12
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Satija, Rahul; Farrell, Jeffrey A; Gennert, David et al. (2015) Spatial reconstruction of single-cell gene expression data. Nat Biotechnol 33:495-502

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