Increasing evidence indicates that aberrations in neural stem cell proliferation and early neurogenesis are critically involved in the pathogenesis of neurodevelopmental and psychiatric disorders. Despite being implicated in pathophysiology of several neurological diseases, the mechanisms through which human kinome controls neurogenesis and how its dysfunction manifests in disease remain major gaps in the field of neurodevelopmental biology. In this proposal, we will investigate the role of an autism susceptibility gene, TAOK2, which encodes a serine threonine kinase, in human neural stem cell development and function. Both loss-of-function and activating TAOK2 mutations have been associated with autism spectrum disorders (ASD). Further, TAOK2 is one of the genes in the 16p11.2 genomic locus, copy number variation (CNV) of which is the most prevalent genetic risk factor associated with ASD. While work by us and others has demonstrated compelling evidence that TAOK2 is important for neuronal and synaptic development, the role of TAOK2 in human neural progenitor cell (NPC) development and differentiation has not been investigated. Further, the contribution of TAOK2 in the pathology associated with 16p11.2 copy number variation is unknown. Based on the strength of our preliminary findings, the central hypothesis of this research proposal is that TAOK2 kinase orchestrates a signaling hub at the centrosome that regulates human neural progenitor stem cell development, and that perturbation of this signaling pathway contributes to pathogenesis of ASD. We will elucidate the role of TAOK2 in NPC development through use of 2D and 3D human induced pluripotent stem cell (hiPSC) models (Aim1). Next, mechanisms through which TAOK2 regulates ciliary growth and signaling will be determined using super-resolution imaging and biochemical approaches (Aim2). The contribution of TAOK2 in the ciliary defects observed in patient-derived NPCs from 16p11.2 deletion and duplication carriers will be determined through application of quantitative proteomics and genome editing techniques (Aim3). Utilizing a combination of innovative approaches and human disease relevant model systems, we seek to understand how TAOK2 kinase signaling mediates neural stem cell development, and how perturbations in its signaling pathways contribute to the clinical neuropathology of 16p11.2 CNV. !
Precise control of neural stem cell proliferation and differentiation is critical for human brain development and function. Using innovative approaches integrating stem cell technology, genome editing, proteomics and super- resolution microscopy in a human relevant model system, we will investigate the role of an autism susceptibility gene, TAOK2 kinase, in neural stem cell proliferation and differentiation, as well as elucidate how its dysfunction contributes to signaling deficits in neural progenitor cells derived from patients with clinically diagnosed autism spectrum disorder. Findings from these studies will increase our understanding of the complex mechanisms that guide and regulate early human neurogenesis, and will inform on potential future targets for the development of novel therapeutic interventions for neurodevelopmental diseases.
