Section 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. 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. As a postdoctoral fellow in Dr. Yuh-Nung Jan?s laboratory at UCSF, I gained skills in neurobiology, mass spectrometry, and chemical-genetics in addition to my graduate background in cell biology and biochemistry. During the K99 award period, I identified the role of TAOK2 in maturation of dendritic spines, synapse localization and compartmentalization of NMDA-receptor mediated calcium influx. Additionally, I mapped the direct neuronal substrates of TAOK2 and found that Septin 7 (Sept7) phosphorylation was required for maturation of dendritic spines through a phosphorylation dependent interaction with scaffold protein PSD95. With the new training and information acquired in the K99 phase, I will extend the scope of my research in the R00 phase: 1) systematic investigation of TAOK2 localization during spine development using super-resolution STORM imaging, 2) characterization of the TAOK2 pathway in ASD pathology using iPSC derived neurons from 16p11.2 deletion patients and 3) phosphoproteomic analysis of 16p11.2 CNV iPSC-derived neurons to identify global changes caused by imbalances in TAOK2 dosage, which may reveal clinically relevant insights into the pathogenesis of ASD. The support afforded by the R00 award will greatly facilitate my long-term goal as an independent investigator to elucidate signaling pathways involved in dendritic spine formation during normal and disease 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.
|Caudron, Fabrice; Yadav, Smita (2018) Meeting report - shining light on septins. J Cell Sci 131:|