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CORDIS

Molecular Principles of Mammalian Axonemal Dynein Assembly

Project description

Insight into motile cilia assembly

From fertilization to our last breath, motile cilia, tiny microtubule-based projections from the cell’s surface, are essential to our health. Cilia movement is powered by masses of molecular motors, known as axonemal dyneins, which convert energy into microtubule bending. These mighty machines are precisely assembled from many different components. This EU-funded CiliaCircuits project will investigate how the cell manufactures these motors in time and space. It aims to understand how the cell builds the appropriate number of protein components and assemble them in the right motor type. In the long-term, it is hoped that CiliaCircuits will identify novel molecular switches in this process leading to effective therapeutics for motile ciliopathies.

Objective

Motile cilia are tiny microtubule-based projections which create fluid flow and are essential to human health. Cilia movement is powered by coordinated action of complex macromolecular motors, the axonemal dyneins. During differentiation, as cells produce hundreds of motile cilia, millions of dynein subunits must be pre-assembled in the cytoplasm into very large complexes in the correct stoichiometry which are then trafficked into growing cilia. This poses a sizeable challenge for the cell in terms of allocation of a significant fraction of the global translational machinery for streamlined assembly of dyneins within a crowded cellular space.

The key question remains: How does the cell know how much is enough? This is an extreme example of a common problem in cell biology. Responsive and adaptive mechanisms must exist to prevent futile expenditure of cellular resources in making a surplus of large molecules like dyneins that may also pose a risk of toxic aggregation. While a well-defined transcriptional code for induction of cilia motility genes exists, the translational dynamics and subsequent feedback circuitry coordinating dynein pre-assembly with ciliogenesis remain unexplored.

The molecular logic underlying the construction of motile cilia assembly are still not fully understood. The ambitious nature of CiliaCircuits proposes to use super-resolution and systems approaches to elucidate key mechanisms regulating this process in health and disease.

Human genetics tells us that making cilia motile is a complex process. To date, almost 40 genes have been implicated in primary ciliary dyskinesia (PCD), the disease of motile cilia, for which there is no cure. The long-term vision is to understand this dynamic control operating over a specialized proteome in time and space in order to develop effective PCD therapeutics and identify additional candidate genes involved in this translation regulation.

Fields of science