Role of Autism Susceptibility Gene, TAOK2 kinase, and its novel substrates in Synaptogenesis

Investigator: Smita Yadav, PhD
Sponsor: NIH National Institute of Mental Health

Location(s): United States


TAOK2 kinase is implicated in dendritic spine formation and is one of the affected genes in the 16p11.2 deletion associated with autism spectrum disorders (ASD). Using innovative strategies, this study aims to identify neuronal targets of TAOK2 kinase and determine their role in synaptic function. By utilizing neurons derived from 16p11.2 deletion patient-derived iPSCs, I will investigate the role of TAOK2 in synaptogenesis and how its abnormal dosage may contribute to the pathogenesis of ASD, thereby providing insight into the role of kinase signaling in synaptic development and disease.

Dendritic spines are specialized actin-rich protrusions that serve as primary recipients of most excitatory synapses in the brain. Spines are extremely dynamic, exhibiting diverse structural and functional changes during development, in response to stimuli, as well as in learning and memory. While there is substantial evidence that several neurodevelopmental and psychiatric diseases converge on a common theme of aberrant spine formation, the mechanisms of spine formation and how its dysfunction relates to disease is unclear. TAOK2 is a serine/threonine kinase implicated in neuronal development, and is one of the genes present in the 16p11.2 genomic locus. Deletion of this region is the most common risk factor associated with autism spectrum disorder (ASD). Despite its relevance in neuronal development and to ASD, the physiological neuronal substrates of TAOK2 kinase are not known. It is unclear how TAOK2 signaling mediates spine development and how an imbalance in TAOK2 gene dosage might contribute to neuronal and behavioral alterations associated with ASD. Using a combination of innovative approaches, this proposal aims to delineate the mechanistic role of TAOK2 kinase during synaptogenesis and to understand how dysfunction in this signaling pathway might contribute to disease.