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Investigating a role of Cdkl5 in cortical development involving the primary cilium


About This PhD Project

Project Description

Project Code: 2020-SIDB-10

Our project aims at studying a novel link between Cyclin-dependent kinase-like 5 (CDKL5) and primary cilia in the development of the cerebral cortex. Pathogenic CDKL5 mutations are the cause of CDKL5 deficiency disorder (CDD), a developmental encephalopathy characterized by early-onset epilepsy and severe intellectual disability1. The identification of CDKL5 mutations represented a first step in understanding the underlying pathomechanisms, but our knowledge of CDKL5 controlled cellular processes lacks behind. Recently, CDKL5 was shown to control the length of the primary cilium2 and to phosphorylate the centriolar satellite protein CEP1313, a regulator of ciliary assembly. Primary cilia are cellular antennas acting as signalling hubs in development and tissue homeostasis. Defects in the structure and/or function underlie a group of syndromes referred to as ciliopathies and can lead to intellectual disability4. Several ciliary genes have also been associated with autism spectrum disorder. Taken together, these findings raise the intriguing possibility that ciliary defects downstream of CDKL5 contribute to CDD pathogenesis.

This project will investigate a link between CDKL5 and primary cilia by analysing ciliary roles in neural stem cells of the cerebral cortex in mice deficient for Cdkl5. Super-resolution imaging and electron microscopy analyses will help to identify defects in cilia structure. Quantitative live cell imaging in cortical stem cells will be used to monitor cilia stability and function. Additionally. immunofluorescence stainings will be used to characterise the properties of cortical stem cells and to investigate the signalling function of the primary cilium, in particular Sonic hedgehog signalling, a key regulator of corticogenesis. The project will also compare cortical development in Cdkl5 and Cep131 mutants, available in the Mill lab. Employing our common expertise on cilia and neural development, this study will reveal how cilia act downstream of CDKL5 in corticogenesis thereby highlighting a novel and convergent disease mechanism.

References

1. Fehr, S., et al. The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy. Eur J Hum Genet 21, 266-273 (2013).

2. Canning, P., et al. CDKL Family Kinases Have Evolved Distinct Structural Features and Ciliary Function. Cell reports 22, 885-894 (2018).

3. Munoz, I.M., et al. Phosphoproteomic screening identifies physiological substrates of the CDKL5 kinase. The EMBO journal 37(2018).

4. Valente, E.M., Rosti, R.O., Gibbs, E. & Gleeson, J.G. Primary cilia in neurodevelopmental disorders. Nature reviews. Neurology 10, 27-36 (2014).

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