The broad goal of this work is to understand morphogenesis of the vertebrate embryo and, in particular, to understand the formation of the vertebrate gut. The hope is that the knowledge we glean will ultimately provide insights into the developmental defects leading to congenital malformations. There has been great progress in recent years in understanding the molecular cues orchestrating gut development. However, relatively less attention has been given to the roles of physical forces in shaping the tissues of the gut. This study attempts to identify the mechanical factors involved in the initial formation of the early gut, and to integrate the understanding of those forces with the activity of signaling molecules that mediate the process. We will start by defining the physical basis of cell movements during hind gut formation. Live imaging microscopy will be used to define the kinematics of cell movement in the gut. Physical experiments will be used to determine the location and directionality of mechanical forces in the endoderm. Fibroblast growth factors are key signals directing cell movements of other tissues and the posterior embryo at the same time as the hindgut is forming. Molecular and genetic perturbations will be used to establish the effects of Fgf signaling on the kinematics of cell movement in the forming gut and to determine the pathways through which Fgf signaling acts in this tissue. Finally, a computational model will be used to gain a quantitative understanding of the mechanics of gut tube formation. Together, this work will substantially increase our understanding of the key initial steps by which the vertebrate gut is formed.

Public Health Relevance

This Project combines imaging, physical force measurements and gene manipulation to understand how the gut tube forms from a sheet of epithelial cells in the developing embryo. Proper formation of the gut tube is critical for all subsequent steps of intestinal morphogenesis, including fitting the coils of the gut into the abdomen without impinging on other organs. Failure in this process can lead to twisting of the gut tube and pinching of the blood supply to the gut, conditions with dire consequences for the affected individual.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD089934-01
Application #
9205846
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Mukhopadhyay, Mahua
Project Start
2017-02-01
Project End
2022-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
1
Fiscal Year
2017
Total Cost
$411,458
Indirect Cost
$168,710
Name
Harvard Medical School
Department
Genetics
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115