Region-Specific Myelin Pathology in Mice Lacking the Golli Products of the Myelin Basic Protein Gene

Abstract

The myelin basic protein (MBP) gene encodes two families of proteins, the classic MBP constituents of myelin and the golli-MBPs, the function of which is less well understood. In this study, targeted ablation of the golli-MBPs, but not the classic MBPs, resulted in a distinct phenotype unlike that of knock-outs (KOs) of the classic MBPs or other myelin proteins. Although the golli KO animals did not display an overt dysmyelinating phenotype, they did exhibit delayed and/or hypomyelination in selected areas of the brain, such as the visual cortex and the optic nerve, as determined by Northern and Western blots and immunohistochemical analysis with myelin protein markers. Hypomyelination in some areas, such as the visual cortex, persisted into adulthood. Ultrastructural analysis of the KOs confirmed both the delay and hypomyelination and revealed abnormalities in myelin structure and in some oligodendrocytes. Abnormal visual-evoked potentials indicated that the hypomyelination in the visual cortex had functional consequences in the golli KO brain. Evidence that the abnormal myelination in these animals was a consequence of intrinsic problems with the oligodendrocyte was indicated by an impaired ability of oligodendrocytes to form myelin sheets in culture and by the presence of abnormal Ca 2ϩ transients in purified cortical oligodendrocytes studied in vitro. The Ca 2ϩ results reported in this study complement previous results implicating golli proteins in modulating intracellular signaling in T-cells. Together, all these findings suggest a role for golli proteins in oligodendrocyte differentiation, migration, and/or myelin elaboration in the brain.

Mice with Conditional Inactivation of Fibroblast Growth Factor Receptor-2 Signaling in Oligodendrocytes Have Normal Myelin But Display Dramatic Hyperactivity when Combined with Cnp1 Inactivation

“…Because various mouse mutants exhibit deficits in the number of OLs and/or myelination only in specific regions of the CNS [e.g., fyn (Sperber et al, 2001); pdgf-A (Fruttiger et al, 1999); Golli MBP (Jacobs et al, 2005); chemokine receptor Cxcr2 (PadovaniClaudio et al, 2006)], we examined multiple regions (cortex, corpus callosum, fornix/fimbria, olfactory bulb, striatum, thalamus, brainstem, and cerebellum) of Fgfr2 conditional knock-out mice for defects in OL differentiation and myelination (Fig. 4).…”

Increased Expression of Golli Myelin Basic Proteins Enhances Calcium Influx into Oligodendroglial Cells

“…OLs and their function are impaired by the selective ablation of golli proteins (Jacobs et al, 2005). The golli knock-out (KO) animals suffer from delayed and reduced myelination in selective regions of the brain, such as the visual cortex and forebrain.…”

“…The golli knock-out (KO) animals suffer from delayed and reduced myelination in selective regions of the brain, such as the visual cortex and forebrain. Impaired formation of myelin sheets in primary cultures of cortical OLs (Jacobs et al, 2005) indicated that at least part of this hypomyelination is caused by intrinsic problems with the OLs. Similar results were found in a new transgenic mouse called JOE (J37 golli overexpressor) in which the golli J37 isoform is overexpressed specifically in OLs under the control of a classic MBP promoter (Martin et al, 2007).…”

Inflammatory Proprotein Convertase-Matrix Metalloproteinase Proteolytic Pathway in Antigen-presenting Cells as a Step to Autoimmune Multiple Sclerosis

“…The rabbit polyclonal antibodies to the Golli portion of Golli-MBP and to the human PC2 and MMP-25 were kindly provided by Drs. Celia and Anthony Campagnoni (UCLA) (27), Robert Day (University of Sheerbrooke, Quebec, Canada), and Rafael Fridman (Wayne State University, Detroit, MI), respectively.…”