P0 Glycoprotein Overexpression Causes Congenital Hypomyelination of Peripheral Nerves

Abstract

We show that normal peripheral nerve myelination depends on strict dosage of the most abundantly expressed myelin gene, myelin protein zero (Mpz). Transgenic mice containing extra copies of Mpz manifested a dose-dependent, dysmyelinating neuropathy, ranging from transient perinatal hypomyelination to arrested myelination and impaired sorting of axons by Schwann cells. Myelination was restored by breeding the transgene into the Mpz-null background, demonstrating that dysmyelination does not result from a structural alteration or Schwann cell-extrinsic effect of the transgenic P0 glycoprotein. Mpz mRNA overexpression ranged from 30–700%, whereas an increased level of P0 protein was detected only in nerves of low copy-number animals. Breeding experiments placed the threshold for dysmyelination between 30 and 80% Mpz overexpression. These data reveal new points in nerve development at which Schwann cells are susceptible to increased gene dosage, and suggest a novel basis for hereditary neuropathy.

Resetting translational homeostasis restores myelination in Charcot-Marie-Tooth disease type 1B mice

“…On the contrary, and confirming our previous observations (Pennuto et al, 2008), P0oe nerves did not show an enrichment for genes related to UPR, suggesting that the ER stress is not caused by the overexpression of P0 by itself, but to the MpzS63del mutation. Surprisingly, despite the fact that the P0oe nerves are hypomyelinated (Wrabetz et al, 2000), we did not see a significant downregulation of genes related to lipid or cholesterol biosynthesis (Table S4); the main down-regulation was for genes involved in cell growth and morphogenesis (Fig. S3), confirming that developmental hypomyelination in P0oe and S63del mice result from different pathomechanisms.…”

“…Third, the activation of the UPR requires the P0 mutation. The transcriptome of nerves from transgenic mice that overexpress P0wt at levels similar to P0S63del (Wrabetz et al, 2000) did not reveal any increase in genes related to ER stress. Fourth, the UPR has been identified of mutant P0S63del in the Schwann cell ER was clearly reduced (Fig.…”

“…To address which transcriptional changes are mutation-and neuropathy-specific, we analyzed the transcriptome of P28 sciatic nerves from mice overexpressing P0wt at levels comparable to P0S63del (P0oe line 80.4; Wrabetz et al, 2000). P0oe mice manifest a hypomyelinating neuropathy, similar to were functionally related, such as stress response, protein folding, or protein catabolism.…”

“…P0S63del transgenic mice (Wrabetz et al, 2006), P0-overexpressing (oe) mice (line 80.4; Wrabetz et al, 2000), Chop-null mice (Zinszner et al, 1998), and Gadd34 c/c mice (Novoa et al, 2003) have been described previously. P0S63del, P0oe, and Chop-null mice were maintained on the FVB/N background, whereas Gadd34 c/c mice, initially on a C57BL/6 background, were backcrossed for at least six generations onto the FVB/N background before initiation of experiments.…”

“…Sciatic nerves from WT and transgenic mice were dissected and immediately frozen in liquid nitrogen. Proteins were extracted and analyzed as previously described (Wrabetz et al, 2000). Mouse monoclonal antibodies recognized -tubulin (1:500; Sigma-Aldrich), ATF6 (1:1,000; Imgenex,), MBP (1:5,000; Covance), and MAG (1:1,000; EMD Millipore).…”