Apical constriction is a cell shape change that drives morphogenetic events in diverse animal systems, including neural tube formation in vertebrates. An understanding of the mechanisms by which cells shrink their apical domains can address fundamental questions about how animal embryos are shaped, and it can lay a foundation for future diagnosis and prevention of human neural tube closure defects, which are among the most common and serious human birth defects. The long-term goal toward which this project contributes is to understand how forces are transmitted with spatial and temporal precision to shape cells and tissues in developing organisms. This goal will be approached using Caenorhabditis elegans as a model system. Gastrulation in C. elegans begins with two endodermal precursor cells (EPCs) undergoing apical constriction, moving from the embryo's surface to the interior, at the 26-28 cell stage. Experiments have determined that actomyosin contractions begin well before apical domains begin to shrink, and that only later do the edges of the apical surfaces begin to narrow in concert with actomyosin contractions-implying that the key connection between the two is not constitutive. The objective of this proposal is to understand the mechanisms that lie at the heart of how cells change shape in an in vivo, developmental context. Our proposed experiments capitalize on strengths of the model system, in which relevant molecules can be identified, and in which mechanisms can be unraveled by a combination of diverse experimental tools.
The aims of the project are to (1) dissect the mechanisms by which the edges of the cells'apical surfaces become linked to pre-existing actomyosin contractions, triggering the shrinking of cells'apical domains, (2) determine the role of a protein that appears on the surfaces of apically constricting cells as apical constriction begins, and (3) integrate genetic studies with the mechanistic studies above, by identifying and studying new proteins involved in apical constriction by the mechanisms above. Successful completion of these aims will reveal key mechanisms underlying apical constriction, an important developmental process. The work has the potential to establish a paradigm for developmental control of cytoskeletal mechanisms, to establish a new mechanism for initiation of a developmental cell shape change, and to identify new molecules that could be relevant to morphogenesis in diverse animal systems including neural tube closure in human development.

Public Health Relevance

This proposal focuses on understanding the mechanisms of apical constriction, which drives morphogenetic events in diverse animal systems, including neural tube formation in vertebrates. Defects in closure of the neural tube are frequent in humans, comprising one of the leading classes of birth defects, and occurring annually in approximately 300,000 newborns worldwide. An understanding of the mechanisms by which cells shrink their apical domains and become internalized can lay a foundation for future diagnosis and prevention of human neural tube closure defects.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM083071-05A1
Application #
8438574
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Hoodbhoy, Tanya
Project Start
2008-06-01
Project End
2016-08-31
Budget Start
2012-09-30
Budget End
2013-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$298,362
Indirect Cost
$98,362
Name
University of North Carolina Chapel Hill
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Linden, Lara M; Gordon, Kacy L; Pani, Ariel M et al. (2017) Identification of regulators of germ stem cell enwrapment by its niche in C. elegans. Dev Biol 429:271-284
Goldstein, Bob; Zallen, Jennifer A (2017) Cell polarity and morphogenesis: new technologies and new findings. Mol Biol Cell 28:699-700
Dickinson, Daniel J; Schwager, Francoise; Pintard, Lionel et al. (2017) A Single-Cell Biochemistry Approach Reveals PAR Complex Dynamics during Cell Polarization. Dev Cell 42:416-434.e11
Dickinson, Daniel J; Goldstein, Bob (2016) CRISPR-Based Methods for Caenorhabditis elegans Genome Engineering. Genetics 202:885-901
Heppert, Jennifer K; Goldstein, Bob (2016) Remodelling germ cells by intercellular cannibalism. Nat Cell Biol 18:1267-1268
Sullivan-Brown, Jessica L; Tandon, Panna; Bird, Kim E et al. (2016) Identifying Regulators of Morphogenesis Common to Vertebrate Neural Tube Closure and Caenorhabditis elegans Gastrulation. Genetics 202:123-39
Tintori, Sophia C; Osborne Nishimura, Erin; Golden, Patrick et al. (2016) A Transcriptional Lineage of the Early C. elegans Embryo. Dev Cell 38:430-44
Heppert, Jennifer K; Dickinson, Daniel J; Pani, Ariel M et al. (2016) Comparative assessment of fluorescent proteins for in vivo imaging in an animal model system. Mol Biol Cell 27:3385-3394
Marston, Daniel J; Higgins, Christopher D; Peters, Kimberly A et al. (2016) MRCK-1 Drives Apical Constriction in C. elegans by Linking Developmental Patterning to Force Generation. Curr Biol 26:2079-89
Goldstein, Bob (2016) Sydney Brenner on the Genetics of Caenorhabditis elegans. Genetics 204:1-2

Showing the most recent 10 out of 36 publications