microRNAs (miRNAs) encode ~22nt small RNAs that regulate deadenylation, translation, and decay of their target mRNAs. With the potential to regulate more that 30% of the human genes, miRNAs play fundamental roles in every aspect of biology from human development, to human disease including neuropsychiatric disorders and cancer. The long-term goal of our research is to understand how miRNAs regulate gene expression to orchestrate early embryogenesis, using zebrafish as a model system. In particular, this proposal focuses on how microRNAs regulate potent signaling molecules to control cell migration in two different contexts during development: lateral line migration and angiogenesis using zebrafish as a model system. Our preliminary studies have used single microRNA knock down and mutants in the microRNA processing pathway indicate that disrupting miR-1 and miR-430 function causes i) abnormal migration of the lateral line primordium (a model for placode migration in vertebrates) and ii) increased migration during angiogenesis (in the intersegmental vessels, ISV). This proposal combines embryological manipulations and live imaging, to understand how miR-1 regulate endothelial cell migration during angiogenesis Aim 1 and understand how miR-430 ensures that different migratory paths driven by the chemokine signaling sdf1a remain separated during development to avoid mis-targeted migration Aim 2. In summary, the proposed experiments have the long term goal of understanding i) how miRNAs regulate individual miRNA targets to orchestrate embryonic development during cell migration, and angiogenesis, ii) how they modulate the expression of potent signaling molecules to ensure the appropriate level of signaling between tissues.

Public Health Relevance

microRNA are small non-coding RNAs that have important regulatory roles in the genome with far reaching roles from human development to cancer. This proposal studies how these microRNAs control the expression of potent migration cues to regulate migration of different cells types in the developing vertebrate embryo to ensure accurate targeting and avoid mis migration.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM081602-06A1
Application #
8438978
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Hoodbhoy, Tanya
Project Start
2007-08-01
Project End
2017-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
6
Fiscal Year
2013
Total Cost
$316,350
Indirect Cost
$126,350
Name
Yale University
Department
Genetics
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Staton, Alison A; Knaut, Holger; Giraldez, Antonio J (2011) miRNA regulation of Sdf1 chemokine signaling provides genetic robustness to germ cell migration. Nat Genet 43:204-11
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