Exploration of physiological functions of mammalian septins with genetically engineered mouse lines

Septins是进化上保守的聚合GTP酶，如微管蛋白和肌动蛋白的主要细胞骨架核苷酸结合蛋白，然而，它们在后生动物中的生理功能在很大程度上是未知的。为解决这一问题：1）我们已经建立了一个条件性SEPT 7敲除小鼠系，并发现septins通过HDAC 6介导的脱乙酰化负调节微管稳定性来促进树突和轴突发育。2)我们建立了朊病毒启动子驱动的SEPT 4转基因小鼠，并发现SEPT 4（帕金森病中聚集的帕金底物）的慢性超负荷导致小鼠行为改变，但不会导致神经退行性变。除了小鼠品系和本研究中创建的一组试剂外，这些和其他发现将有助于了解septin功能在生理相关背景下与其他细胞骨架系统相关的细胞/分子机制。

Septins are evolutionarily conserved polymerizing GTPases like the major cytoskeletal nucleotide-binding proteins of tubulins and actins, however, their physiological functions in metazoans are largely unknown. To address this: 1) We have established a line of conditional SEPT7 knockout mice and uncovered that septins promote dendrite and axon development by negatively regulating microtubule stability via HDAC6-mediated deacetylation. 2) We established prion-promoter-driven SEPT4 transgenic mice and uncovered that chronic overload of SEPT4, a parkin substrate that aggregates in Parkinson's disease, causes behavioral alterations but not neurodegeneration in mice. These and other findings, in addition to mouse lines and a set of reagents created in this study, will help understand cellular/molecular mechanisms of septin functions in relation to other cytoskeletal systems in physiologically relevant contexts.