New principles in collective cell migration during Drosophila organ development

Cell migration drives most developmental processes, wound closure, as well as immune response. It constitutes a hallmark of cancer. Especially in tumour metastasis and development, cells rely on collective cell migration. Much knowledge about the exact mechanics of collective motility was gathered f...

Full description

Saved in:
Bibliographic Details
Main Author: Bischoff, Maik Christian
Contributors: Bogdan, Sven (Prof. Dr.) (Thesis advisor)
Format: Dissertation
Language:English
Published: Philipps-Universität Marburg 2020
Normale und Pathologische Physiologie
Subjects:
Online Access:PDF Full Text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Cell migration drives most developmental processes, wound closure, as well as immune response. It constitutes a hallmark of cancer. Especially in tumour metastasis and development, cells rely on collective cell migration. Much knowledge about the exact mechanics of collective motility was gathered from a few model systems in which migration processes can be precisely analysed and genetically, mechanically, and pharmacologically influenced. This work aims to extend the existing range of such models by establishing a new ex vivo system for collective cell migration. The testis of Drosophila is surrounded by a layer of smooth-like muscles. The precursors of these cells, multinucleated myotubes, have to get to the testis and to migrate toward its distal end during pupal development. Organ-culture conditions were determined, allowing to recapitulate the process ex vivo. Thereby, the mechanical rules by which myotubes migrate could be assessed. Testis myotubes seem to use a lamellipodium-independent migration mode that is based entirely on the dynamics of filopodia-like protrusions. In previous studies, a chemoattractive effect mediated by the fibroblast growth factor receptor (FGFR) Heartless (Htl) was discussed, besides its likely role in regulating the number of myoblasts on the genital disc and its possible role in connecting testis and seminal vesicles. The results obtained in this work oppose a chemoattractive function but rather suggest a general role of Htl in the initiation of cell migration. Mathematical and statistical analysis of migration trajectories in the background of genetic, mechanical, and pharmacological perturbation suggest a self-regulating process. The observed dynamics reveal similarities to contact inhibition of locomotion (CIL) since cell-cell contacts provide crucial information for individual cells to enable directionality. Cells seem to inhibit substrate adhesion in filopodia in a contact-dependent manner. This process appears to be controlled by the Rho-GTPases Rac2 and Cdc42. As a result of the contact-dependent loss of adhesion, there is a net-movement into the cell-free space. At the same time, N-Cadherin seems to ensure that cells maintain adhesion to one another. Therefore, there is no repulsive migration as in CIL. Finally, supracellular RhoA/Rock-dependent actomyosin cables appear to support cohesion by closing gaps in the cell cluster at concavely curved edges. These mechanisms presumably result in a process in which all available space is evenly covered by myotubes. Myotube motility appears to be dependent on proteolytic degradation of the matrix. For this reason, in the future, the newly established ex vivo system could allow studying the collective dynamics of invasive migration in detail.
Physical Description:187 Pages
DOI:https://doi.org/10.17192/z2020.0424