X-linked microtubule-associated protein, Mid1, regulates axon development

Significance The gene responsible for the X-linked form of Opitz syndrome (OS), Midline-1 (MID1), encodes an E3 ubiquitin ligase and was reported to guide the degradation of the catalytic subunit of protein phosphatase 2A (PP2Ac). But whether and how it is involved in neural development is unclear. We demonstrate here that Mid1-dependent PP2Ac turnover is involved in axon development. Knocking down or knocking out Mid1 not only promotes axon growth and branching in vitro, but also accelerates axon elongation and disrupts the pattern of callosal projection in mouse cortex. These defects can be reversed by down-regulating the accumulated PP2Ac in Mid1-depleted cells. Dysfunction of this Mid1–PP2Ac pathway may underlie neural symptoms of OS patients. Opitz syndrome (OS) is a genetic neurological disorder. The gene responsible for the X-linked form of OS, Midline-1 (MID1), encodes an E3 ubiquitin ligase that regulates the degradation of the catalytic subunit of protein phosphatase 2A (PP2Ac). However, how Mid1 functions during neural development is largely unknown. In this study, we provide data from in vitro and in vivo experiments suggesting that silencing Mid1 in developing neurons promotes axon growth and branch formation, resulting in a disruption of callosal axon projections in the contralateral cortex. In addition, a similar phenotype of axonal development was observed in the Mid1 knockout mouse. This defect was largely due to the accumulation of PP2Ac in Mid1-depleted cells as further down-regulation of PP2Ac rescued the axonal phenotype. Together, these data demonstrate that Mid1-dependent PP2Ac turnover is important for normal axonal development and that dysregulation of this process may contribute to the underlying cause of OS.

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