How do mutations in dynein motor components cause birth defects?

Research Opportunity
PhD, Masters by Research, Honours, Master of Biomedical Science
Project Status
Future
Department
Medicine and Radiology
Location
St Vincent's Hospital
Supervisor Email Number Webpage
A/Prof Jorg Heierhorst Personal web page

Project Details

Dyneins are large protein complexes that move cargos along microtubules in the cell. Mutations in several subunits of the cytoplasmic Dynein-2 complex have recently been linked to severe birth defects, so-called short-rib/polydactyly syndromes, in humans.

Affected patients have very short bones, including a very narrow rib cage, which leads to severe breathing difficulties and, often, early death in newborns. It is known that Dynein-2 functions specifically in cilia, short antenna-like organelles on the top of cells that receive and process critical developmental signals in embryos. However, the precise molecular mechanisms of how Dynein-2 functions in the processing of signals within cilia, and how this is affected by short-rib/polydactyly mutations, remain unclear.

We have generated mouse mutants for one of the Dynein-2 subunits, the light chain DYNLL1, which replicate the key feature of human short-rib/polydactyly syndromes: very short bones and extra fingers. An important advantage of our mice is that they represent the first animal model where a Dynein-2 subunit can be removed in a cell-type and tissue-specific manner. This allows us to maintain intact Dynein-2 in the rib-cage, and thus to avoid the lethal breathing difficulties, and enables us to study its functions much more deeply than possible with the existing Dynein-2 mutants, which all die at or before birth.

The aim of this project is to understand how loss of DYNLL1 affects the activity of the Dynein-2 complex and its signaling function in cilia, using cells from our Dynll1 knockout mice. The project will involve microscopy analysis (including electron microscopy) of cilia formation, and cilia-specific transport, in normal and mutant cells, as well as microscopy and protein analyses of cilia-specific transport and signal processing events. It is expected that the results will provide an improved understanding of how Dynein-2 defects cause birth defects in humans.

This project is conducted in St Vincent’s Institute of Medical Research, Molecular Genetics Unit.

Research Opportunities

This research project is available to PhD, Masters by Research, Honours, Master of Biomedical Science students to join as part of their thesis.
Please contact the supervisor to discuss your options.

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Faculty Research Themes

Child Health

School Research Themes

Child Health in Medicine



Key Contact

For further information about this research, please contact a supervisor.

Department

Medicine and Radiology

Research Node

St Vincent's Hospital