Dissecting the molecular crosstalk between mechanotransduction and primary cilia in models of congenital valvulopathies

Primary cilia are versatile microtubule-based protrusions located at the surface of nearly every cell of the human body. In addition to important functions in adults, PC are important regulators of embryonic development. PC are considered as dynamic cellular antenna that sense environmental cues via multiple signalling pathways in different tissues and across developmental stages. Their microtubule-based axoneme can remodel by assembling, maintaining, and disassembling in response to environmental stimuli during tissue differentiation. Nevertheless, the link between PC ultrastructure and its signalling activities is unclear. Furthermore, while PC composition seems to be conserved among cell types, it is unclear why ciliary defects alter specific tissues like the retina or the heart and not others. Hence, understanding the mechanisms through which mutated proteins alter PC structure and signalling is essential to understand how ciliary defects can lead to pathologies, including CHD.

Cardiac cells sense mechanical forces through mechanotransduction. For instance, we recently found that stretch sensitive channels and mechanosensitive purinergic signalling are key to cardiogenesis. These and our further preliminary evidence prompted us to question the current paradigm of cilia related function during cardiac morphogenesis, and to formulate an alternative hypothesis: We postulate that cardiac primary cilia and cilia related proteins control cardiac cells properties required for successful morphogenesis by modulating these mechanosensitive pathways.

The proposal has two complimentary objectives:
Objective 1. To identify the mechanosensitive pathway(s) acting in the EdCs in response to mechanical forces and relationship with ciliary proteins.
Objective 2. To define the cellular functions of ciliary proteins in the process of cardiac valve formation with a specific focus on mechanosensitive processes.

We will have a particular focus on the ciliary protein Dzip1. Dzip1...