MTCL1 plays an essential role in maintaining Purkinje neuron axon initial segment

Abstract

The axon initial segment ( AIS ) is a specialized domain essential for neuronal function, the formation of which begins with localization of an ankyrin‐G (AnkG) scaffold. However, the mechanism directing and maintaining AnkG localization is largely unknown. In this study, we demonstrate that in vivo knockdown of microtubule cross‐linking factor 1 ( MTCL 1) in cerebellar Purkinje cells causes loss of axonal polarity coupled with AnkG mislocalization. MTCL 1 lacking MT ‐stabilizing activity failed to restore these defects, and stable MT bundles spanning the AIS were disorganized in knockdown cells. Interestingly, during early postnatal development, colocalization of MTCL 1 with these stable MT bundles was observed prominently in the axon hillock and proximal axon. These results indicate that MTCL 1‐mediated formation of stable MT bundles is crucial for maintenance of AnkG localization. We also demonstrate that Mtcl1 gene disruption results in abnormal motor coordination with Purkinje cell degeneration, and provide evidence suggesting possible involvement of MTCL 1 dysfunction in the pathogenesis of spinocerebellar ataxia. image Microtubule‐stabilizing protein, MTCL 1, is required for maintaining ankyrin‐G localization to the AIS region of Purkinje cells. Analysis of mutant mice shows the importance of MTCL 1 for Purkinje cell maintenance and cerebellar function. MTCL 1 is required for maintaining ankyrin‐G localization to the AIS region of Purkinje cells. MTCL 1 is required for formation of stable microtubule bundles at the AIS region. Microtubule‐stabilizing ability of MTCL 1 is essential for the maintenance of ankyrin‐G localization. Mtcl1 mutant mice show motor coordination defects with Purkinje cell degeneration.