Pyruvate dehydrogenase E2 complex

This project is now closed

Kinase signalling pathways in brain development

Project supervisor: Sila Konur Ultanir (Developmental Neurobiology)

Dendrite morphogenesis and synapse formation are critical for establishing the neural circuitry to enable proper brain function. Kinases regulate most, if not all, cellular processes by phosphorylating their substrates thus altering their activity. The role of the numerous kinase signalling cascades in neural development and the molecular mechanisms of action of these kinases are not well-understood.

Cyclin- dependent kinase like 5 (Cdkl5) is a member of cyclin-dependent kinase family of serine/threonine protein kinases. Mutations disrupting a single copy of this X-linked gene in girls cause severe neurological problems that prevent normal development of physical and mental activities such as walking or talking. CDKL5 is highly expressed in the brain during development and in adult. It is predominantly a neuronal protein which shuttles between nucleus and cytoplasm in an activity dependent manner.

The function of CDKL5 in synaptic development and dendritic spine morphogenesis and the downstream effectors of CDKL5 in neuronal dendrite development are unknown. Moreover, CDKL5 mutation phenotypes highly resemble the more common Rett Syndrome however the relation between CDKL5 and the Rett Syndrome gene MeCP2 is not clear. Understanding CDKL5’s molecular functions and downstream effectors could help identify targets for treatment of these neurodevelopmental disorders. Moreover, studying the causes of this syndrome could be invaluable in discovering how brain develops normally.

The goals of this project are:

  1. To identify the phosphorylation targets of CDKL5 in the mouse brain using analog sensitive kinase based covalent capture method (Ultanir et al, 2012)
  2. To investigate the role of CDKL5 and its novel substrates in synaptic development in neuronal cultures and in vivo.

The project will use a chemical genetics, confocal imaging and electrophysiology in cultured neurons and in vivo analysis by using in utero electroporations in mice and transgenic mice to uncover the targets and role of CDKL5 in neuronal development.

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