Kinase Signaling in Neurodevelopment and Disease
From the birth of a neuron to its integration into functional neuronal networks, signaling cascades mediated by kinases regulate all aspects of neuronal development. Not surprisingly, aberrations in kinase pathways, therefore, are associated with the pathophysiology of several major neurological disorders. Despite genomic evidence implicating kinases in neurological diseases, our understanding about how the human kinome controls neuronal development, how its dysfunction manifests in disease, and whether kinases can be targeted with specificity for therapeutic purposes is limited. The Yadav laboratory is interested in investigating the kinase signaling pathways that are important for neuronal development as well as in understanding how their dysfunction leads to neurodevelopmental and psychiatric disorders such as autism and schizophrenia.
Our lab utilizes a combination of powerful approaches in chemical-genetics, induced pluripotent stem cell (iPSC) technology, high-resolution live cell imaging and quantitative proteomics to investigate the role of kinases and their downstream targets in neuronal development and disease.
TAOK2 is one of the genes in the 16p11.2 genomic locus. Copy number variation in this 550Mbp region comprising 29 genes is associated with both autism spectrum disorder (ASD) and schizophrenia. TAOK2 is important for neuronal development, specifically for formation of dendritic spines and elaboration of dendritic arbor; however, its role in pathogenesis of ASD and schizophrenia is unclear. We recently found that TAOK2 is required for spine-synapse formation in hippocampal neurons. Using a chemical-genetic approach that allows mapping of direct kinase substrates, we have identified the physiological neuronal targets of TAOK2 and found that among them Sept7, a cytoskeletal protein, is required for synapse maturation (Yadav et al., 2017). We are currently investigating the mechanisms by which abnormal gene dosage of TAOK2 kinase in 16p11.2 deletion and duplication contributes to neuronal alterations leading to ASD. Unraveling the functional role of TAOK2 kinase and its identified substrates will allow us to examine the consequence of abnormal kinase signaling in 16p11.2 deletion and duplication ASD patients.