Abstract:

CDKL5 is an X-linked serine/threonine kinase highly expressed in the mammalian brain. Loss-of- function mutations in CDKL5 cause a rare neurodevelopmental disorder named CDKL5 Deficiency Disorder (CDD). Patients with CDD have early-onset seizures, severe neurodevelopmental deficits and they require life-long care. To determine the roles of CDKL5 in brain development, we aimed to identify CDKL5’s substrates in the brain using chemical genetic and proteomics approaches. Our work revealed multiple physiological substrates of CDKL5 in the brain including microtubule binding proteins EB2, MAP1S and ARHGEF2 and the voltage-gated calcium channel, Cav2.3.

We generated phosphomutant mouse models for MAP1S and Cav2.3 to study the roles of these phosphorylations in mouse brain. We find that MAP1S phosphorylation affects its microtubule binding, dendritic microtubule stability, tubulin tyrosination and dynein-mediated transport on neuronal dendrites leading to defective synapse development and learning. In addition, our work in Cav2.3 shows that the loss of Cav2.3 phosphorylation leads to gain of function of the channel, similar to the functional effects of the ultrarare CACNA1E mutations in epilepsy patients. We postulate that inhibition of Cav2.3 can be beneficial for CDD. More recently, we revealed that CDKL2 phosphorylates multiple CDKL5 substrates in brain, thus upregulation of CDKLs can be a therapeutic avenue.

Bio:

Sila Ultanir is a Senior Group Leader at the Francis Crick Institute, London, UK. Sila completed her undergraduate education in Bilkent University, Turkey. She did her PhD on neuroscience, focusing on dendrite development and synaptogenesis in Dr Rafael Yuste's lab at Columbia University, New York. She then moved to Dr Anirvan Ghosh's laboratory at the University of California, San Diego, where she studied the role of NMDA receptors on dendritic spine development. Sila then joined Dr Yuh-Nung Jan's laboratory at University of California, San Francisco and worked on kinase signaling mechanisms on dendrite development in collaboration with Dr Kevan Shokat's laboratory. She started her lab at NIMR, Mill Hill, London in 2013.