Man-made systems are assembled out of components with physical properties engineered to perform specific functions within the final assembly. By contrast, biological systems self- assemble, using genetic control to continuously regulate tissue biomechanics and tissue function throughout embryogenesis and organogenesis. Genetic analyses have revealed many of the underlying principles of pattern formation and cell differentiation during development. However, neither the biomechanics of development nor the genetic control of these biomechanics is well understood. The tailbud is the posterior leading edge of the growing vertebrate embryo and contains bipotential neural/mesodermal stem cells as well as spinal cord and mesodermal progenitors. This proposal focuses on the roles of cell-cell and cell-extracellular matrix (ECM) adhesion in defining tissue biomechanics in the extending tailbud. It is hypothesized that Fibronectn- dependent mechanical coupling between these tissues maintains parallel orientation of their posteriorly directed forces. This coupling increases the net posteriorly directed force. Within the posterior paraxial mesoderm, it is hypothesized that Fibronectin fibrillogenesi and remodeling drives tissue assembly. Tissue assembly requires integration of cell-cell and cell-ECM adhesion via Cadherin 2 which regulates Fibronectin matrix dynamics and produces a phase transition within the tissue from a viscoelastic fluid to a viscoelastic solid In Aim I-A, the lab will examine whether inter-tissue adhesion between the paraxial mesoderm and notochord promotes posterior elongation.
In Aim I -B, the lab will quantify Fibronectin matrix dynamics in the paraxial mesoderm and test whether Fibronectin fibrillogenesis helps drive paraxial mesoderm elongation.
In Aim II, the lab examines the roles of cadherin 2 and integrin ?5 in regulating the transition in Fibronectin matrix and cell motion dynamics during the assembly of the paraxial mesoderm.
In Aim III, the lab measures the contribution of these cell and tissue level processes to the generation of posteriorly directed force in the extending tailbud.

Public Health Relevance

This project seeks to understand how cells and connective tissues interact to determine tissue architecture and dynamics. These interactions are important for cell differentiation and tissue homeostasis. Here, tissue dynamics are studied using zebrafish live imaging and systems level analysis of the image data.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01GM107385-01A1
Application #
8695630
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Hoodbhoy, Tanya
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Yale University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
City
New Haven
State
CT
Country
United States
Zip Code
06510
McMillen, Patrick; Chatti, Veena; Jülich, Dörthe et al. (2016) A Sawtooth Pattern of Cadherin 2 Stability Mechanically Regulates Somite Morphogenesis. Curr Biol 26:542-9
McMillen, Patrick; Holley, Scott A (2015) Integration of cell-cell and cell-ECM adhesion in vertebrate morphogenesis. Curr Opin Cell Biol 36:48-53
Jülich, Dörthe; Cobb, Garrett; Melo, Ana M et al. (2015) Cross-Scale Integrin Regulation Organizes ECM and Tissue Topology. Dev Cell 34:33-44
McMillen, Patrick; Holley, Scott A (2015) The tissue mechanics of vertebrate body elongation and segmentation. Curr Opin Genet Dev 32:106-11