The Protein Tyrosine Phosphatase Shp2 Regulates Oligodendrocyte Differentiation and Early Myelination and Contributes to Timely Remyelination

Abstract

Shp2 is a nonreceptor protein tyrosine phosphatase that has been shown to influence neurogenesis, oligodendrogenesis, and oligodendrocyte differentiation. Furthermore, Shp2 is a known regulator of the Akt/mammalian target of rapamycin and ERK signaling pathways in multiple cellular contexts, including oligodendrocytes. Its role during later postnatal CNS development or in response to demyelination injury has not been examined. Based on the current studies, we hypothesize that Shp2 is a negative regulator of CNS myelination. Using transgenic mouse technology, we show that Shp2 is involved in oligodendrocyte differentiation and early myelination, but is not necessary for myelin maintenance. We also show that Shp2 regulates the timely differentiation of oligodendrocytes following lysolecithin-induced demyelination, although apparently normal remyelination occurs at a delayed time point. These data suggest that Shp2 is a relevant therapeutic target in demyelinating diseases such as multiple sclerosis. In the present study, we show that the protein phosphatase Shp2 is an important mediator of oligodendrocyte differentiation and myelination, both during developmental myelination as well as during myelin regeneration. We provide important insight into the signaling mechanisms regulating myelination and propose that Shp2 acts as a transient brake to the developmental myelination process. Furthermore, we show that Shp2 regulates oligodendrocyte differentiation following demyelination and therefore has important therapeutic implications in diseases such as multiple sclerosis.

Protein Kinase C Activation Drives a Differentiation Program in an Oligodendroglial Precursor Model through the Modulation of Specific Biological Networks

“…In particular, CNP is a well-known abundant marker expressed in pre-myelinating and mature OLs, involved in RNA metabolism of highly myelinating regions and in OLs process formation [ 31 ]. Moreover, RTN4 is a protein extensively expressed in OLs, contributing to the differentiation of these cells [ 58 ], while Shp2 (or PPTN11) is a crucial controller of normal OPCs generation, differentiation and myelination, likely through MAPK-signaling regulation [ 33 , 59 ]. In this regard, MAP2K1 and MAPK1 are included in this upregulated network.…”

Excitable Axonal Domains Adapt to Sensory Deprivation in the Olfactory System

“…We performed immunohistochemical labeling using a free-floating slices protocol modified from previous studies (Ahrendsen et al, 2018; et al, 2018). Slices were processed in batches to reduce variability and facilitate comparison.…”

Excitable axonal domains adapt to sensory deprivation in the olfactory system

“…We performed immunohistochemical labeling using a free-floating slices protocol modified from previous studies (Gould et al, 2018;Ahrendsen et al, 2018). Slices were processed in batches to reduce variability and facilitate comparison.…”

“…For sectioning, brains were embedded in 4% low-melt agarose for stability and cut in 1X PBS on a vibratome (Ted Pella, Redding, California) into 300µm thick coronal sections encompassing the region 2.45-3.05mm anterior to the bregma suture. Further processing was performed as previously described (Ahrendsen et al, 2018). Briefly, using a PELCO Biowave Pro Tissue Processor (Ted Pella, Redding, California), the tissue was rinsed in 100 mM cacodylate buffer and then postfixed in a reduced osmium mixture consisting of 1% osmium tetroxide and 1.5% potassium ferrocyanide followed by 1% osmium tetroxide alone.…”

“…A g-ratio of 1 indicates an unmyelinated axon, while computational modeling studies propose an optimal g-ratio of~0.77, balancing energy demands of the structure, space, and axonal conduction (Chomiak and Hu, 2009). To calculate axon diameter, we fit the measured perimeter of the polygon to the equivalent circle (perimeter = circumference) and calculated the resulting diameter (Diameter = circumference / ) (Ahrendsen et al, 2018).…”