Normal CNS Myelination in Transgenic Mice Overexpressing MHC Class I H-2Ld in Oligodendrocytes

doi:10.1006/mcne.2001.1011

Molecular and Cellular Neuroscience

Volume 18, Issue 2, August 2001, Pages 221-234

https://doi.org/10.1006/mcne.2001.1011 Get rights and content

Abstract

In demyelinating diseases, such as multiple sclerosis, an upregulation of MHC class I expression is thought to contribute to oligodendrocyte/myelin damage. In order to investigate potential physiological consequences of upregulated MHC class I expression in oligodendrocytes, we generated transgenic mice that overexpress H-2L^d under the control of the proteolipid protein (PLP) promoter (PLP-L^d mice). We focused our studies on the MHC class I molecule H-2L^d, because of its unique intracellular transport characteristics. In the CNS of PLP-L^d mice, H-2L^d was expressed by oligodendrocytes. Furthermore, H-2L^d protein was transported to and expressed on the surface of oligodendrocytes. Most importantly, this upregulation of MHC class I expression in the CNS of PLP-L^d mice did not by itself result in a de- or dysmyelinating phenotype. These transgenic mice are likely to provide a unique and novel tool for the analysis of potential roles of MHC class I-mediated mechanisms in demyelinating pathologies.

References (69)

K. Ainger et al.
Transport and localization elements in myelin basic protein mRNA
J. Cell Biol.
(1997)
K. Asotra et al.
Protein kinase C activity modulates myelin gene expression in enriched oligodendrocytes
J. Neurosci.
(1993)
K.D. Baerwald et al.
Developing and mature oligodendrocytes respond differently to the immune cytokine interferon-gamma
J. Neurosci. Res.
(1998)
K.D. Baerwald et al.
Major histocompatibility complex heavy chain accumulation in the endoplasmic reticulum of oligodendrocytes results in myelin abnormalities
J. Neurosci. Res.
(2000)
J.C. Beck et al.
Slower processing, weaker beta 2-M association, and lower surface expression of H-2L^d are influenced by its amino terminus
J. Immunol.
(1986)
M. Brahic et al.
Genetics of susceptibility to Theiler's virus infection
Bioassays
(1998)
P. Chomczynski et al.
Single-step method of RNA isolation by acid guanidine thiocyanate-phenol-chloroform extraction
Anal. Biochem.
(1987)
J.R. Cook et al.
Induction of peptide-specific CD8⁺ CTL clones in β₂-microglobulin-deficient mice
J. Immunol.
(1995)
J.G. Corbin et al.
Targeted CNS expression of interferon-gamma in transgenic mice leads to hypomyelination, reactive gliosis, and abnormal cerebellar development
Mol. Cell. Neurosci.
(1996)
J.L. Dean et al.
The 3′ untranslated region of tumor necrosis factor alpha mRNA is a target of the mRNA-stabilizing factor HuR
Mol. Cell. Biol.
(2001)

B. Fuss et al.

Phosphodiesterase I, a novel adhesion molecule and/or cytokine involved in oligodendrocyte function

J. Neurosci.

(1997)

B. Fuss et al.

Purification and analysis of in vivo-differentiated oligodendrocytes expressing the green fluorescent protein

Dev. Biol.

(2000)

M.V. Gardinier et al.

Characterization of myelin proteolipid mRNAs in normal and jimpy mice

Mol. Cell. Biol.

(1986)

T.H. Hansen et al.

Studies of two antigenic forms of L^d with disparate beta 2-microglobulin (beta 2m) associations suggest that beta 2m facilitate the folding of the alpha 1 and alpha 2 domains during de novo synthesis

J. Immunol.

(1988)

M. Hirayama et al.

Induction of human leukocyte antigen-A,B,C and -DR on cultured human oligodendrocytes and astrocytes by human γ-interferon

Neurosci. Lett.

(1986)

B. Hogan et al.

Manipulating the Mouse Embryo: A Laboratory Manual

(1994)

M.S. Horwitz et al.

Detailed in vivo analysis of interferon-γ induced major histocompatibility complex expression in the central nervous system: Astrocytes fail to express major histocompatibility complex class I and II molecules

Lab. Invest.

(1999)

M.S. Horwitz et al.

Primary demyelination in transgenic mice expressing interferon-γ

Nat. Med.

(1997)

H. Jiang et al.

Proteolipid protein mRNA stability is regulated by axonal contact in the rodent peripheral nervous system

J. Neurobiol.

(2000)

A. Jurewicz et al.

MHC class I-restricted lysis of human oligodendrocytes by myelin basic protein peptide-specific CD8 T lymphocytes

J. Immunol.

(1998)

S.A. Kalwy et al.

Mechanisms of myelin basic protein and proteolipid protein targeting in oligodendrocytes (Review)

Mol. Membr. Biol.

(1994)

L. Klein et al.

Shaping of the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cells

Nat. Med.

(2000)

P.A. Krieg et al.

Functional messenger RNAs are produced by SP6 in vitro transcription of cloned cDNAs

Nucleic Acids Res

(1984)

S. Kyuwa et al.

Acute and late disease induced by murine coronavirus, strain JHM, in a series of recombinant inbred strains between BALB/cHeA and STS/A mice

Microb. Pathog.

(1992)

L.A. Lampson et al.

Monoclonal antibody analysis of MHC expression in human brain biopsies: Tissue ranging from “histologically normal” to that showing different levels of glial tumor involvement

J. Immunol.

(1986)

S.M. LeVine et al.

Developmental expression of proteolipid protein and DM20 mRNAs and proteins in the rat brain

Dev. Neurosci.

(1990)

C. Linington et al.

A novel myelin-associated glycoprotein defined by a mouse monoclonal antibody

J. Neuroimmunol.

(1984)

C.F. Lucchinetti et al.

A quantitative analysis of oligodendrocytes in multiple sclerosis lesions

Brain

(1999)

C.F. Lucchinetti et al.

The controversy surrounding the pathogenesis of the multiple sclerosis lesion

Mayo Clin. Proc.

(1997)

W. Ma et al.

Interferon-gamma rapidly increases peptide transporter (TAP) subunit expression and peptide transport capacity in endothelial cells

J. Biol. Chem.

(1997)

W.B. Macklin et al.

Mutations in the myelin proteolipid protein gene alter oligodendrocyte gene expression in jimpy and jimpymsd mice

J. Neurochem.

(1991)

P.T. Massa et al.

Cell type-specific regulation of major histocompatibility complex (MHC) class I gene expression in astrocytes, oligodendrocytes and neurons

Glia

(1993)

G. Mavria et al.

Transcriptional regulation of MHC class I gene expression in rat oligodendrocytes

Biochem. J.

(1998)

K.D. McCarthy et al.

Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue

J. Cell Biol.

(1980)

Cited by (26)

Crossing boundaries: Interplay between the immune system and oligodendrocyte lineage cells
2021, Seminars in Cell and Developmental Biology
Citation Excerpt :
Similarly to IFNγ delivery to the developing CNS, overexpression of the MHC-I molecule H-2K in OLs (under the myelin basic protein promoter) also led to a hypomyelination phenotype, driven by a delay in developmental myelination and/or oligodendrocyte cell death [41,42]. Nevertheless, overexpression of another MHC-I molecule, H-2L under the proteolipid protein (Plp) promoter, did not present a disfunction in myelination [43]. Beta 2 microglobulin (B2m), which forms a complex with the heavy chain MHC-I molecule and the peptide antigen, is only weakly associated with H-2L, which could explain the differences in phenotype between these mice strains [43].
Oligodendrocytes and their progenitors are glial cells in the central nervous system, which have been mainly implicated with the homeostatic roles of axonal myelin ensheathment but serve as targets of the peripheral immune system attack in the context of diseases like multiple sclerosis. This view of oligodendroglia as passive bystanders with no immunological properties was first challenged in the 1980s when it was reported that the cytokine interferon γ could induce the gene expression of the major histocompatibility complexes (MHC) class I and II. While the physiological role of this induction was controversial for decades to follow, recent studies suggest that oligodendroglia survey their environment, respond to a larger array of cues and can indeed exert immunomodulatory functions, which are particularly relevant in the context of neurodegeneration and demyelinating diseases. The alternative functionality of oligodendroglia not only regulates immune cell responses, but also hinders remyelination, and might thereby be key to understanding MS disease pathology and promoting regeneration after immune-mediated demyelination.
PERK activation preserves the viability and function of remyelinating oligodendrocytes in immune-mediated demyelinating diseases
2014, American Journal of Pathology
Citation Excerpt :
We have generated PLP/Fv2E-PERK transgenic mice that allow temporally controlled activation of PERK signaling specifically in oligodendrocytes in the absence of ER stress.11 These mice express Fv2E-PERK, an artificial PERK that is generated by fusing the eIF2α kinase effector domain of PERK to a polypeptide containing two modified FK506 binding domains (Fv2E),22 under the control of the mouse PLP transcriptional control region.23,24 We have demonstrated that PLP/Fv2E-PERK mice express the transgene product Fv2E-PERK specifically in oligodendrocytes and that the activity of Fv2E-PERK is tightly controlled by administration of the dimerizer AP20187.11
Remyelination occurs in multiple sclerosis (MS) lesions but is generally considered to be insufficient. One of the major challenges in MS research is to understand the causes of remyelination failure and to identify therapeutic targets that promote remyelination. Activation of pancreatic endoplasmic reticulum kinase (PERK) signaling in response to endoplasmic reticulum stress modulates cell viability and function under stressful conditions. There is evidence that PERK is activated in remyelinating oligodendrocytes in demyelinated lesions in both MS and its animal model, experimental autoimmune encephalomyelitis (EAE). In this study, we sought to determine the role of PERK signaling in remyelinating oligodendrocytes in MS and EAE using transgenic mice that allow temporally controlled activation of PERK signaling specifically in oligodendrocytes. We demonstrated that persistent PERK activation was not deleterious to myelinating oligodendrocytes in young, developing mice or to remyelinating oligodendrocytes in cuprizone-induced demyelinated lesions. We found that enhancing PERK activation, specifically in (re)myelinating oligodendrocytes, protected the cells and myelin against the detrimental effects of interferon-γ, a key proinflammatory cytokine in MS and EAE. More important, we showed that enhancing PERK activation in remyelinating oligodendrocytes at the recovery stage of EAE promoted cell survival and remyelination in EAE demyelinated lesions. Thus, our data provide direct evidence that PERK activation cell-autonomously enhances the survival and preserves function of remyelinating oligodendrocytes in immune-mediated demyelinating diseases.
Functional recovery of callosal axons following demyelination: a critical window
2009, Neuroscience
Citation Excerpt :
Cuprizone is a well described gliotoxic agent that alters the functions of OL mitochondria resulting in cell death. Eight wks old transgenic C57BL/6 female mice expressing enhanced green fluorescent proteins (EGFP) under the proteolipid protein (PLP) promoter (PLP_EGFP), (Fuss et al., 2001; Mallon et al., 2002) were fed with 0.2% cuprizone diet for 1.5 to 6 wks (demyelination group, DM: 1.5 wkDM, 3 wkDM, and 6 wkDM), resulting in demyelination of the CC. The decrease in myelin was assessed by myelin oligodendrocyte glycoprotein (MOG) immunolabelling intensity in the delineated CC.
Axonal dysfunction as a result of persistent demyelination has been increasingly appreciated as a cause of functional deficit in demyelinating diseases such as multiple sclerosis. Therefore, it is crucial to understand the ultimate causes of ongoing axonal dysfunction and find effective measures to prevent axon loss. Our findings related to functional deficit and functional recovery of axons from a demyelinating insult are important preliminary steps towards understanding this issue. Cuprizone diet for 3–6 wks triggered extensive corpus callosum (CC) demyelination, reduced axon conduction, and resulted in loss of axon structural integrity including nodes of Ranvier. Replacing cuprizone diet with normal diet led to regeneration of myelin, but did not fully reverse the conduction and structural deficits. A shorter 1.5 wk cuprizone diet also caused demyelination of the CC, with minimal loss of axon structure and nodal organization. Switching to normal diet led to remyelination and restored callosal axon conduction to normal levels. Our findings suggest the existence of a critical window of time for remyelination, beyond which demyelinated axons become damaged beyond the point of repair and permanent functional loss follows. Moreover, initiating remyelination early within the critical period, before prolonged demyelination-induced axon damage ensues, will improve functional axon recovery and inhibit disease progression.
Assaying the functional effects of demyelination and remyelination: Revisiting field potential recordings
2009, Journal of Neuroscience Methods
The occurrence and histopathological characteristics of demyelination and neurodegeneration have been well described in different demyelinating mouse models. However, histopathological analysis is limiting in that it is unable to describe the functional consequences of demyelination and recovery after remyelination. Establishing the functional correlates of axon demyelination and remyelination is an important goal and can be used to measure axon function and develop neuroprotective therapies. This report describes a previously established, simple, easily applied method of electrophysiological measurement that can characterize white matter axonal dysfunction following demyelination and potential recovery after remyelination. It is designed to study in vitro stimulated compound action potentials in the corpus callosum of superfused brain slices at various time points and can be similarly used on white matter tracts in the optic nerve, spinal cord and cerebellum. Since behavioral testing can be performed prior to the brain slice electrophysiology, and the recorded slices can be post-fixed and subjected to histological analysis, correlates between behavior, axon function, and pathology can be determined. A temporal pattern of white matter functional deterioration and recovery can also be established to study mechanisms of demyelination-induced white matter injury and repair.
Chapter 1 Genetic Dissection of Neural Circuits and Behavior in Mus musculus
2009, Advances in Genetics
Citation Excerpt :
For example, the use of promoters like Nestin (Cheng et al., 2004), PrP (Fischer et al., 1996), and neuron‐specific enolase (Forss‐Petter et al., 1990) result in transgene expression throughout the brain but not in other parts of the body. For further restriction to specific brain regions or cell types, researchers used more specific promoters, including the α‐CaMKII promoter for postnatal forebrain specific expression in excitatory neurons (Abel et al., 1997; Mayford et al., 1996), glial fibrillary acidic protein (GFAP) for astrocyte‐specific expression (Brenner et al., 1994; Casper et al., 2007; Halassa et al., 2009; Pascual et al., 2005), proteolipid protein (PLP) oligodendrocyte‐specific expression (Fuss et al., 2001), and L7 for expression in cerebellar Purkinje cells and retinal bipolar neurons (Oberdick et al., 1990). Large‐scale screening projects have been initiated to determine the brain expression patterns of a tremendous number of specific promoters, allowing researchers to choose a promoter that targets a particular class of neurons, such as those that produce a specific neurotransmitter, or express a specific receptor.
One of the major challenges in the field of neurobiology is to elucidate the molecular machinery that underlies the formation and storage of memories. For many decades, genetic studies in the fruit fly (Drosophila melanogaster) have provided insight into the role of specific genes underlying memory storage. Although these pioneering studies were groundbreaking, a transition to a mammalian system more closely resembling the human brain is critical for the translation of basic research findings into therapeutic strategies in humans. Because the mouse (Mus musculus) shares the complex genomic and neuroanatomical organization of mammals and there is a wealth of molecular tools that are available to manipulate gene function in mice, the mouse has become the primary model for research into the genetic basis of mammalian memory. Another major advantage of mouse research is the ability to examine in vivo electrophysiological processes, such as synaptic plasticity and neuronal firing patterns during behavior (e.g., the analysis of place cell activity). The focus on mouse models for memory research has led to the development of sophisticated behavioral protocols capable of exploring the role of particular genes in distinct phases of learning and memory formation, which is one of the major accomplishments of the past decade. In this chapter, we will give an overview of several state of the art genetic approaches to study gene function in the mouse brain in a spatially and temporally restricted fashion.
Down-regulation of polysialic acid is required for efficient myelin formation
2007, Journal of Biological Chemistry
Citation Excerpt :
Generation of PLP-PST Transgenic Mice−Mouse ST8SiaIV was amplified by PCR using oligonucleotides PSTsense (5′-GCAAGCTTCCATGCGCTCAATTAGAAAACG-3′) and PSTanti (5′-GCTCTAGATTATTGCTTCATGCACTTTCC-3′), digested with HindIII and XbaI (introduced restriction sites are underlined in the primer sequences), treated with Klenow enzyme (fill-in reaction), and ligated into the PmeI site of the PLP promoter cassette (19) (kindly provided by W. B. Macklin (Cleveland Clinic Foundation)) (see Fig. 1A).
Oligodendrocyte precursor cells modify the neural cell adhesion molecule (NCAM) by the attachment of polysialic acid (PSA). Upon further differentiation into mature myelinating oligodendrocytes, however, oligodendrocyte precursor cells down-regulate PSA synthesis. In order to address the question of whether this down-regulation is a necessary prerequisite for the myelination process, transgenic mice expressing the polysialyltransferase ST8SiaIV under the control of the proteolipid protein promoter were generated. In these mice, postnatal down-regulation of PSA in oligodendrocytes was abolished. Most NCAM-120, the characteristic NCAM isoform in oligodendrocytes, carried PSA in the transgenic mice at all stages of postnatal development. Polysialylated NCAM-120 partially co-localized with myelin basic protein and was present in purified myelin. The permanent expression of PSA-NCAM in oligodendrocytes led to a reduced myelin content in the forebrains of transgenic mice during the period of active myelination and in the adult animal. In situ hybridizations indicated a significant decrease in the number of mature oligodendrocytes in the forebrain. Thus, down-regulation of PSA during oligodendrocyte differentiation is a prerequisite for efficient myelination by mature oligodendrocytes. Furthermore, myelin of transgenic mice exhibited structural abnormalities like redundant myelin and axonal degeneration, indicating that the down-regulation of PSA is also necessary for myelin maintenance.

View all citing articles on Scopus

¹: To whom correspondence and reprint requests should be addressed. Fax: (804) 828 9477. E-mail: [email protected].

View full text

Regular ArticleNormal CNS Myelination in Transgenic Mice Overexpressing MHC Class I H-2Ld in Oligodendrocytes

Abstract

Transport and localization elements in myelin basic protein mRNA

J. Cell Biol.

Protein kinase C activity modulates myelin gene expression in enriched oligodendrocytes

J. Neurosci.

Developing and mature oligodendrocytes respond differently to the immune cytokine interferon-gamma

J. Neurosci. Res.

Major histocompatibility complex heavy chain accumulation in the endoplasmic reticulum of oligodendrocytes results in myelin abnormalities

J. Neurosci. Res.

Slower processing, weaker beta 2-M association, and lower surface expression of H-2Ld are influenced by its amino terminus

J. Immunol.

Genetics of susceptibility to Theiler's virus infection

Bioassays

Single-step method of RNA isolation by acid guanidine thiocyanate-phenol-chloroform extraction

Anal. Biochem.

Induction of peptide-specific CD8+ CTL clones in β2-microglobulin-deficient mice

J. Immunol.

Targeted CNS expression of interferon-gamma in transgenic mice leads to hypomyelination, reactive gliosis, and abnormal cerebellar development

Mol. Cell. Neurosci.

The 3′ untranslated region of tumor necrosis factor alpha mRNA is a target of the mRNA-stabilizing factor HuR

Mol. Cell. Biol.

Phosphodiesterase I, a novel adhesion molecule and/or cytokine involved in oligodendrocyte function

J. Neurosci.

Purification and analysis of in vivo-differentiated oligodendrocytes expressing the green fluorescent protein

Dev. Biol.

Characterization of myelin proteolipid mRNAs in normal and jimpy mice

Mol. Cell. Biol.

Studies of two antigenic forms of Ld with disparate beta 2-microglobulin (beta 2m) associations suggest that beta 2m facilitate the folding of the alpha 1 and alpha 2 domains during de novo synthesis

J. Immunol.

Induction of human leukocyte antigen-A,B,C and -DR on cultured human oligodendrocytes and astrocytes by human γ-interferon

Neurosci. Lett.

Manipulating the Mouse Embryo: A Laboratory Manual

Detailed in vivo analysis of interferon-γ induced major histocompatibility complex expression in the central nervous system: Astrocytes fail to express major histocompatibility complex class I and II molecules

Lab. Invest.

Primary demyelination in transgenic mice expressing interferon-γ

Nat. Med.

Proteolipid protein mRNA stability is regulated by axonal contact in the rodent peripheral nervous system

J. Neurobiol.

MHC class I-restricted lysis of human oligodendrocytes by myelin basic protein peptide-specific CD8 T lymphocytes

J. Immunol.

Mechanisms of myelin basic protein and proteolipid protein targeting in oligodendrocytes (Review)

Mol. Membr. Biol.

Shaping of the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cells

Nat. Med.

Functional messenger RNAs are produced by SP6 in vitro transcription of cloned cDNAs

Nucleic Acids Res

Acute and late disease induced by murine coronavirus, strain JHM, in a series of recombinant inbred strains between BALB/cHeA and STS/A mice

Microb. Pathog.

Monoclonal antibody analysis of MHC expression in human brain biopsies: Tissue ranging from “histologically normal” to that showing different levels of glial tumor involvement

J. Immunol.

Developmental expression of proteolipid protein and DM20 mRNAs and proteins in the rat brain

Dev. Neurosci.

A novel myelin-associated glycoprotein defined by a mouse monoclonal antibody

J. Neuroimmunol.

A quantitative analysis of oligodendrocytes in multiple sclerosis lesions

Brain

The controversy surrounding the pathogenesis of the multiple sclerosis lesion

Mayo Clin. Proc.

Interferon-gamma rapidly increases peptide transporter (TAP) subunit expression and peptide transport capacity in endothelial cells

J. Biol. Chem.

Mutations in the myelin proteolipid protein gene alter oligodendrocyte gene expression in jimpy and jimpymsd mice

J. Neurochem.

Cell type-specific regulation of major histocompatibility complex (MHC) class I gene expression in astrocytes, oligodendrocytes and neurons

Glia

Transcriptional regulation of MHC class I gene expression in rat oligodendrocytes

Biochem. J.

Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue

J. Cell Biol.

Regular Article
Normal CNS Myelination in Transgenic Mice Overexpressing MHC Class I H-2L^d in Oligodendrocytes

Slower processing, weaker beta 2-M association, and lower surface expression of H-2L^d are influenced by its amino terminus

Induction of peptide-specific CD8⁺ CTL clones in β₂-microglobulin-deficient mice

Studies of two antigenic forms of L^d with disparate beta 2-microglobulin (beta 2m) associations suggest that beta 2m facilitate the folding of the alpha 1 and alpha 2 domains during de novo synthesis