Molecular Neurophysiology and Biophysics Section, Program in Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Nat Commun. 2013;4:2270. doi: 10.1038/ncomms3270.
Dipeptidyl-peptidase 6 is an auxiliary subunit of Kv4-mediated A-type K(+) channels that, in addition to enhancing channel surface expression, potently accelerates their kinetics. The dipeptidyl-peptidase 6 gene has been associated with a number of human central nervous system disorders including autism spectrum disorders and schizophrenia. Here we employ knockdown and genetic deletion of dipeptidyl-peptidase 6 to reveal its importance for the formation and stability of dendritic filopodia during early neuronal development. We find that the hippocampal neurons lacking dipeptidyl-peptidase 6 show a sparser dendritic branching pattern along with fewer spines throughout development and into adulthood. In electrophysiological and imaging experiments, we show that these deficits lead to fewer functional synapses and occur independently of the potassium channel subunit Kv4.2. We report that dipeptidyl-peptidase 6 interacts with a filopodia-associated myosin as well as with fibronectin in the extracellular matrix. dipeptidyl-peptidase 6 therefore has an unexpected but important role in cell adhesion and motility, impacting the hippocampal synaptic development and function.
二肽基肽酶 6 是 Kv4 介导的 A 型 K(+)通道的辅助亚基，除了增强通道表面表达外，还能显著加速其动力学。二肽基肽酶 6 基因与许多人类中枢神经系统疾病有关，包括自闭症谱系障碍和精神分裂症。在这里，我们利用二肽基肽酶 6 的敲低和基因缺失来揭示其在早期神经元发育过程中形成和稳定树突丝状伪足中的重要性。我们发现缺乏二肽基肽酶 6 的海马神经元在整个发育过程和成年期表现出更稀疏的树突分支模式，并且分支更少。在电生理和成像实验中，我们表明这些缺陷导致功能性突触减少，并且与钾通道亚基 Kv4.2 无关。我们报告二肽基肽酶 6 与丝状伪足相关的肌球蛋白以及细胞外基质中的纤维连接蛋白相互作用。因此，二肽基肽酶 6 在细胞黏附和运动中具有意想不到但重要的作用，影响海马突触的发育和功能。
