Anillin facilitates septin assembly to prevent pathological outfoldings of central nervous system myelin.

Michelle S Erwig,Olaf Jahn,Payam Dibaj,Ingo Heilmann,Ramona B Jung,Mareike Heilmann,Hauke B Werner,Anna M Steyer,Klaus-Armin Nave,Kathrin Kusch,Wiebke Möbius,Julia Patzig

doi:10.7554/elife.43888

Abstract

Myelin serves as an axonal insulator that facilitates rapid nerve conduction along axons. By transmission electron microscopy, a healthy myelin sheath comprises compacted membrane layers spiraling around the cross-sectioned axon. Previously we identified the assembly of septin filaments in the innermost non-compacted myelin layer as one of the latest steps of myelin maturation in the central nervous system (CNS) (Patzig et al., 2016). Here we show that loss of the cytoskeletal adaptor protein anillin (ANLN) from oligodendrocytes disrupts myelin septin assembly, thereby causing the emergence of pathological myelin outfoldings. Since myelin outfoldings are a poorly understood hallmark of myelin disease and brain aging we assessed axon/myelin-units in Anln-mutant mice by focused ion beam-scanning electron microscopy (FIB-SEM); myelin outfoldings were three-dimensionally reconstructed as large sheets of multiple compact membrane layers. We suggest that anillin-dependent assembly of septin filaments scaffolds mature myelin sheaths, facilitating rapid nerve conduction in the healthy CNS.

Highlights

Fast, saltatory nerve impulse conduction in the central nervous system (CNS) of vertebrates is facilitated by the ensheathment of axons with multiple layers of insulating oligodendroglial membrane, termed myelin (Nave and Werner, 2014; Hartline and Colman, 2007)
To address a functional connection between anillin and myelin septins, we first asked if the protein is enriched in CNS myelin
Anillin was detected in myelin when biochemically purified from mouse brains at postnatal day 75 (P75), while it was virtually undetectable in brain lysates when loading the same amount of protein (Figure 1A)

Summary

Introduction

Saltatory nerve impulse conduction in the central nervous system (CNS) of vertebrates is facilitated by the ensheathment of axons with multiple layers of insulating oligodendroglial membrane, termed myelin (Nave and Werner, 2014; Hartline and Colman, 2007). Localized in the non-compacted, adaxonal myelin layer adjacent to the inner-most compacted myelin membrane, myelin septin filaments are assembled from the monomers SEPT2, SEPT4, SEPT7 and SEPT8 in 1:1:2:2 stoichiometry (Patzig et al, 2016a) This marks a canonical but distinct composition of subunits when compared with the higher order structures of septins in other cell types (Barral and Kinoshita, 2008; Dolat et al, 2014). Conditional mouse mutants lacking expression of the Anln-gene in mature oligodendrocytes fail to assemble septin filaments, display large myelin outfoldings similar to those of Sept8-mutant mice (Patzig et al, 2016a) and exhibit reduced nerve conduction velocity. This work establishes a crucial function for anillin-dependent assembly of myelin septin filaments in scaffolding CNS myelin to enable rapid nerve conduction, thereby demonstrating a vital function of anillin unrelated to cytokinesis

Results and discussion

55 ATP1A1

Materials and methods

Funding Funder Deutsche Forschungsgemeinschaft