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Sila Ultanir : Role of CDKL5 in brain development.

Introduction

We propose using our kinase substrate identification method to reveal the substrates and phosphorylation sites of CDKL5.

Cyclin-dependent kinase like 5 (Cdkl5) also known as serine threonine kinase 9 (Stk9) is a member of cyclin-dependent kinase family of serine/threonine protein kinases. Mutations in cdkl5 gene have been associated with severe neurodevelopmental disorders such as Infantile Spasms, West Syndrome and atypical Rett syndrome. Cdkl5 gene is on the X chromosome and mutations in cdkl5 affects girls.

Although rapidly growing evidence implies cdkl5 in these developmental disorders, the current understanding of the biological function of CDKL5 is limited.

CDKL5 is heavily expressed in the brain during development and in adults. In cortical neurons CDKL5 shuttles between nucleus and cytoplasm and loss of CDKL5 function causes reduced dendrite arborisation. 

The function of cdkl5 in synaptic development and dendritic spine morphogenesis has not been investigated. More importantly the molecular mechanisms by which CDKL5 exert its functions are unknown.

A direct and unbiased screen to identify the phosphorylation targets of CDKL5 would address its molecular functions. We propose using our kinase substrate identification method to reveal the substrates of CDKL5 and its phosphorylation sites.

Our next goal is to investigate the significance of CDKL5 and its substrates in neuronal development using morphological and physiological methods in cultures and in mouse models.