Yadav Smita, Oses-Prieto Juan A, Peters Christian J, Zhou Jing, Pleasure Samuel J, Burlingame Alma L, Jan Lily Y, Jan Yuh-Nung
Departments of Physiology, Biochemistry, and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
Mass Spectrometry Facility, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
Neuron. 2017 Jan 18;93(2):379-393. doi: 10.1016/j.neuron.2016.12.006. Epub 2017 Jan 5.
Abnormalities in dendritic spines are manifestations of several neurodevelopmental and psychiatric diseases. TAOK2 is one of the genes in the 16p11.2 locus, copy number variations of which are associated with autism and schizophrenia. Here, we show that the kinase activity of the serine/threonine kinase encoded by TAOK2 is required for spine maturation. TAOK2 depletion results in unstable dendritic protrusions, mislocalized shaft-synapses, and loss of compartmentalization of NMDA receptor-mediated calcium influx. Using chemical-genetics and mass spectrometry, we identified several TAOK2 phosphorylation targets. We show that TAOK2 directly phosphorylates the cytoskeletal GTPase Septin7, at an evolutionary conserved residue. This phosphorylation induces translocation of Septin7 to the spine, where it associates with and stabilizes the scaffolding protein PSD95, promoting dendritic spine maturation. This study provides a mechanistic basis for postsynaptic stability and compartmentalization via TAOK2-Sept7 signaling, with implications toward understanding the potential role of TAOK2 in neurological deficits associated with the 16p11.2 region.
树突棘异常是多种神经发育和精神疾病的表现。TAOK2是16p11.2基因座中的基因之一，其拷贝数变异与自闭症和精神分裂症有关。在此，我们表明TAOK2编码的丝氨酸/苏氨酸激酶的激酶活性是树突棘成熟所必需的。TAOK2缺失导致树突突起不稳定、轴突-突触定位错误以及NMDA受体介导的钙内流的分隔化丧失。使用化学遗传学和质谱法，我们鉴定了几个TAOK2磷酸化靶点。我们表明TAOK2在一个进化保守的残基处直接磷酸化细胞骨架GTP酶Septin7。这种磷酸化诱导Septin7易位至树突棘，在那里它与支架蛋白PSD95结合并使其稳定，促进树突棘成熟。本研究为通过TAOK2-Sept7信号传导实现突触后稳定性和分隔化提供了机制基础，对理解TAOK2在与16p11.2区域相关的神经功能缺损中的潜在作用具有启示意义。
