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Squeezing through the embryo:Dissecting nuclear mechanics during embryonic cell migration

Reference	BB/W017482/1
Principal Investigator / Supervisor	Dr Aparna Ratheesh
Co-Investigators / Co-Supervisors
Institution	University of Warwick
Department	Warwick Medical School
Funding type	Research
Value (£)	431,797
Status	Current
Type	Research Grant
Start date	01/02/2023
End date	31/01/2026
Duration	36 months

Abstract

Embryonic macrophage migration and tissue seeding is essential for accurate animal development and for setting up tissue-resident macrophages which persist into the adulthood. Yet, the mechanisms through which macrophages infiltrate tissues during early embryogenesis are not fully elucidated. Preliminary data that we present in this proposal reveals a previously undescribed mechanistic insight: As Drosophila embryonic macrophages migrate within the extended germband, their nuclei undergoes cycles of nuclear deformation. We propose to use this powerful in vivo 3D confinement model to uncover the nuclear mechanics during embryonic migration and its role in macrophage gene expression. We will first quantitatively describe the permissive physical constraints and instructive mechanical cues from the germband driving nuclear deformations and translocation. We will then elucidate the cellular and molecular force generation and transduction machineries regulating nuclear deformations and translocation. We will further use our experimentally derived nuclear shape changes to theoretically estimate the magnitude and direction of forces driving nuclear mechanics. Finally, using a transcriptomics approach in combination with an ex vivo 3D confiner, we will generate a map of mechanosensitive genes/ understand how nuclear deformation drives changes in macrophage gene expression and migration. By integrating classical genetics with mechanobiology, this proposal seeks to substantially fill a gap in our understanding of how embryonic cells deform their nuclei while migrating in confined environments during development to perform their various functions.

Summary

Macrophages are highly motile immune cells which often act as the first line of defence against pathogens. They also assist in wound healing and clearing up of dead cells and debris and tissue remodelling. All these functions are extremely important to ensure accurate animal development and homeostasis in the adult. They can also be reprogrammed to act in highly detrimental ways, assisting cancer metastasis and exacerbating inflammation. Since their ability to migrate underpins their ability to function accurately, understanding macrophage migration has important implications to our ability to ensure healthy living across the lifespan. We use the macrophages of the common fruit fly Drosophila Melanogaster as a model system to study macrophage migration. Fruit fly macrophages, also called haemocytes, are very like their vertebrate counterparts; they display similar origins and utilize similar mechanisms to migrate. Our recent work using the fruit fly macrophages in the embryo showed that they can squeeze into very dense tissue environments and this ability to migrate under tight confinement is important to ensure macrophage distribution within the embryo. In this proposal, we address the mechanisms through which the macrophage nucleus is moved through tissue barriers. The nucleus which is the repository of the genetic information also happens to be the stiffest organelle in the cell. Hence, moving the nucleus through barriers is not an easy task and nuclear deformation is key to migration under confinement. We have recently discovered that the macrophage nucleus undergoes extensive rearrangements in shape while they move through the embryo. Using a combination of biophysical and genetic experiments as well as cutting edge image analysis and mathematical modelling, we seek to understand the mechanical forces which are generated and transduced to deform and move the nucleus. We also seek to understand how nuclear deformations can in turn affect gene expression and thus macrophage functionality. We anticipate that fundamental principles which govern nuclear mechanics will be conserved across multiple cell types and the results of our proposal will inform studies not only on macrophage migration, but that of other embryonically migrating cell types and even metastatic cancer cells.

Committee	Research Committee C (Genes, development and STEM approaches to biology)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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