Pals1 Is a Major Regulator of the Epithelial-Like Polarization and the Extension of the Myelin Sheath in Peripheral Nerves

Abstract

Diameter, organization, and length of the myelin sheath are important determinants of the nerve conduction velocity, but the basic molecular mechanisms that control these parameters are only partially understood. Cell polarization is an essential feature of differentiated cells, and relies on a set of evolutionarily conserved cell polarity proteins. We investigated the molecular nature of myelin sheath polarization in connection with the functional role of the cell polarity protein pals1 (Protein Associated with Lin Seven 1) during peripheral nerve myelin sheath extension. We found that, in regard to epithelial polarity, the Schwann cell outer abaxonal domain represents a basolateral-like domain, while the inner adaxonal domain and Schmidt-Lanterman incisures form an apical-like domain. Silencing of pals1 in myelinating Schwann cells in vivo resulted in a severe reduction of myelin sheath thickness and length. Except for some infoldings, the structure of compact myelin was not fundamentally affected, but cells produced less myelin turns. In addition, pals1 is required for the normal polarized localization of the vesicular markers sec8 and syntaxin4, and for the distribution of E-cadherin and myelin proteins PMP22 and MAG at the plasma membrane. Our data show that the polarity protein pals1 plays an essential role in the radial and longitudinal extension of the myelin sheath, likely involving a functional role in membrane protein trafficking. We conclude that regulation of epithelial-like polarization is a critical determinant of myelin sheath structure and function.

Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signaling

“…The polarity protein Par-3 is necessary for normal peripheral myelination (23) and can be detected in SC areas of noncompact myelin with a distribution strikingly similar to that of Sirt2 (24). Indeed, fluorescence immunostaining showed colocalization of Sirt2 and Par-3 in SCs and at regular internodal intervals on teased nerve fibers ( Fig.…”

“…On the basis of the identified interaction between Par-3 and the p75 NTR receptor (23), this deficit was mechanistically attributed to mislocalization of p75 NTR at the axo-glial junction, resulting in failed BDNF signal transduction at this site, which is crucial for myelination. Additionally, the polarity proteins Pals1 and Dlg1 also play a role in myelin assembly in vivo (24,41). Indeed, many key polarity proteins are expressed in SCs (24), making it increasingly clear that molecular mechanisms used to establish polarity in epithelia are also operant in SCs.…”

“…Additionally, the polarity proteins Pals1 and Dlg1 also play a role in myelin assembly in vivo (24,41). Indeed, many key polarity proteins are expressed in SCs (24), making it increasingly clear that molecular mechanisms used to establish polarity in epithelia are also operant in SCs. Importantly, manipulation of these proteins does not result in global SC dysfunction, but rather in attenuated myelin thickness and in specific defects of myelin formation (24,41).…”

“…S6C). This result suggests that these proteins colocalize in noncompact myelin in vivo (note that Par-3 also colocalizes with N-cadherin at SL incisures) (23,24). We next examined whether Par-3 was an acetylated protein that could be deacetylated by Sirt2.…”

Quand trop de myélinisation détruit la myéline

“…Dans les nerfs de souris, MTMR2 interagit avec la protéine de polarité cellulaire Disks large homolog 1 (Dlg1), suggérant l'intervention d'un processus de polarisation de la cellule de Schwann lors de la myélinisation. Après avoir étudié la polarisation cellulaire des cellules de Schwann myélinisantes [6], nous avons montré que Dlg1 et MTMR2 participaient à un mécanisme prévenant un excès de [10]. La suppression de Dlg1 n'induit pas d'excès de myélinisation indiquant que, chez ces mutants CMT-4B, Dlg1 n'exerce pas son rôle de frein de la myélinisation.…”