Characterization of SKT/KIAA1217 Synaptic Protein from Mouse Model to Human iPSCs

Synaptic transmission and dendritic spine (DS) formation in excitatory synapses are finely regulated by many intracellular proteins and membrane receptors, most of them participating in the formation of the post-synaptic density (PSD), a membrane-free organelle adjacent to the neuronal post-synaptic plasmatic membrane. Synaptic dysfunctions, due to the abnormal expression or localization of specific components, have been associated with synaptopathies, including cognitive impairments, neurological disabilities and neurodegenerative disorders. In this work, the murine SKT gene emerged as a new relevant component of the synaptic protein complex, by the analysis of SKT gene total knockout (SKT-/-) mice. Moreover, we started the characterization of the human SKT homolog KIAA1217 (hSKT) in human induced pluripotent stem cells (hiPSCs). In murine primary hippocampal cultures, SKT was first found highly expressed in the post-synaptic compartment, and eventually was identified as an interactor of some of the major known post-synaptic proteins, such as PSD-95 and the members of the SHANK family proteins. Primary cultured neurons from SKT-/- neurons displayed a reduced number of total dendritic spines (DSs) along with an increased percentage of immature filopodial DSs compared to the WT controls, suggesting a pivotal role of SKT in the structural and functional organization of the PSD. From preliminary studies, SKT protein resulted expressed also in hiPSCs. Future analyses will allow a deeper understanding of KIAA1217's function in human cortical excitatory neurons derived from iPSCs, generated through direct differentiation by Tet-ON induction of the Ngn2 transcription factor.