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

septin是进化上保守的聚合gtp酶，类似于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。为了解决这个问题：1)我们建立了一条条件SEPT7敲除小鼠系，发现SEPT7通过hdac6介导的去乙酰化负调控微管稳定性，从而促进树突和轴突的发育。2)我们建立了朊病毒启动子驱动的SEPT4转基因小鼠，发现SEPT4（一种帕金森氏病聚集的帕金森底物）的慢性过载导致小鼠行为改变，但不会导致神经变性。这些和其他的发现，以及本研究中创建的小鼠系和一套试剂，将有助于理解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.