Dissecting mechanisms of endocardial cell volume regulation in zebrafish cardiac valve morphogenesis
File(s)
Author(s)
Vagena-Pantoula, Christina
Type
Thesis or dissertation
Abstract
Amongst the mechanisms involved in tissue development, cell volume regulation emerges as an important modulator of morphogenesis. In zebrafish, endocardial cell volume decrease is pivotal for heart valve formation. However, the cellular and molecular mechanisms underlying endocardial cell volume changes remain unknown. Here, I demonstrate that the interplay of the mechanosensitive ion channel Piezo1, the receptor Notch1b and an aquaporin (Aqp) water channel controls endocardial cell volume reduction. I show that Aqp8a.1 is required for endocardial cell volume regulation, and aqp8a.1 mutant larvae display heart valve defects, altered cell polarity and absence of F-actin remodelling. Furthermore, I demonstrate that aqp8a.1 expression is regulated by Notch signalling. Mechanistically, overexpression of Piezo1 using the genetically encoded Piezo1 biosensor GenEPi leads to downregulation of notch1b and subsequently aqp8a.1. At the protein level, the Ca2+-binding calmodulin directly binds to the Aqp8a.1 carboxyl terminus, driving Aqp8a.1 localisation in response to mechanical stimuli. In parallel with these mechanisms, F-actin remodelling through the actin crosslinking protein Marcksl1 arises as an essential event for AVC EdC cell volume reduction. Altogether, this work identifies new effectors of endocardial cell volume changes and heart morphogenesis, thereby increasing our fundamental knowledge on early organogenesis.
Version
Open Access
Date Issued
2024-02-29
Date Awarded
2024-07-01
Copyright Statement
Creative Commons Attribution ShareAlike Licence
License URL
Advisor
Vermot, Julien
Publisher Department
Bioengineering
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)