# Morphogenesis: Biophysics and Genetics of Dorsal Closure

> **NIH NIH R35** · DUKE UNIVERSITY · 2020 · $436,789

## Abstract

Cell sheet morphogenesis plays crucial roles in developmental milestones during vertebrate morphogenesis,
including gastrulation and the formation of the neural tube, the heart, and the palate. It is also essential for
wound healing. Coordination of the cellular machineries and the signaling cascades that drive and regulate
morphogenesis is critical – misregulation results in developmental and wound healing defects that can be fatal.
We focus on the fundamental biology of how cell sheet morphogenesis is powered, regulated and coordinated
during dorsal closure in Drosophila melanogaster. Conservation of molecular, cellular and tissue archictecture
make closure an ideal model system for interrogating the molecular basis of morphogenesis.
During closure, lateral epidermal sheets advance to close a dorsal opening. Closure is amenable to a wide variety
of diverse experimental approaches and we pioneered the study of closure as a model system, especially through
the use of live imaging strategies. We identified four processes that contribute to closure and demonstrated that
no single force that contributes is absolutely required. Thus, closure is robust, resilient and redundant using
molecular components that are conserved across metazoan phylogeny. Our recent work focuses on how ion fluxes
contribute to closure and proposes a thermodynamic model to understand tissue remodeling during closure. We
address how signals from patterning and polarity gene products converge to regulate cell shape and the changes
in cell shape that characterize morphogenesis. We initiated a forward genetic screen that directly assesses the
kinematics of closure and investigates the genetic basis for closure's robustness and resilience. More than 140
genes were previously known to contribute to DC and we have already discovered 23 additional genetic intervals
that are required for closure in a pilot screen of just ¹/? of the fly genome. During the next five years we plan to
use gene discovery to identify new genes that are required for closure. We will use high-resolution 4D imaging
to document quantitatively the cellular shape changes that characterize closure in wild type and mutant animals,
then use biophysical strategies to determine how these new genes contribute to force production and regulation
of closure. Key conceptual gaps we plan to address are what roles embryonic patterning plays in establishing the
cellular and subcellular architectures that characterizes the embryo at the onset of closure and how ion fluxes
contribute to closure. We will investigate the signal (or signals) that triggers the onset of closure and feedback
mechanisms that compensate for genetic or physical insults to the progress of closure. We will continue to
explore how force-generating cytoskeletal components are positioned, coordinated and regulated and study how
adhesion complexes both transmit forces and allow cell movements.
We are uniquely poised to address key extant questions that charac...

## Key facts

- **NIH application ID:** 9962452
- **Project number:** 5R35GM127059-03
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** DANIEL PETER KIEHART
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $436,789
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962452

## Citation

> US National Institutes of Health, RePORTER application 9962452, Morphogenesis: Biophysics and Genetics of Dorsal Closure (5R35GM127059-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9962452. Licensed CC0.

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