Where, when and how much: regulation of myelin proteolipid protein gene expression

Wight, P.A.L.; Dobretsova, Anna

doi:10.1007/s00018-003-3309-z

Cited by 27 publications

(8 citation statements)

References 149 publications

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“…The gene is highly expressed in oligodendrocytes and olfactory ensheathing cells (OECs) (Griffiths et al, 1995; Dickinson et al, 1997), and to a lesser extent in select populations of neurons and additional cell types in the periphery (reviewed in Wight and Dobretsova, 2004). The gene is located on the X chromosome with seven major exons distributed across nearly 16 kb of DNA in human.…”

Section: Introductionmentioning

confidence: 99%

The wmN1 enhancer region in intron 1 is required for expression of human PLP1

Hamdan

Patyal

Kockara

et al. 2018

Glia

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The myelin proteolipid protein gene (PLP1) encodes the most abundant protein present in myelin from the central nervous system (CNS). Its expression must be tightly controlled as evidenced by mutations that alter PLP1 dosage; both overexpression (elevated PLP1 copy number) and lack thereof (PLP1 deletion) result in X-linked genetic disorders in man. However, not much is known about the mechanisms that govern expression of the human gene. To address this, transgenic mice were generated which utilize human PLP1 (hPLP1) sequences (proximal 6.2 kb of 5'-flanking DNA to the first 38 bp of exon 2) to drive expression of a lacZ reporter cassette. LoxP sites were incorporated around a 1.5-kb section of hPLP1 intron 1 since it contains sequence orthologous to the wmN1 region from mouse which, previously, was shown to augment expression of a minimally-promoted transgene coincident with the active myelination period of CNS development. Eight transgenic lines were generated with the parental, 6.2hPLP(+)Z/FL, transgene. All lines expressed the transgene appropriately in brain as evidenced by staining with X-gal in white matter regions and olfactory bulb. Removal of the "wmN1" region from 6.2hPLP(+)Z/FL with a ubiquitously expressed Cre-driver caused a dramatic reduction in transgene activity. These results demonstrate for the first time that the wmN1 enhancer region: (1) is functional in hPLP1; (2) works in collaboration with its native promoter-not just a basal heterologous promoter; (3) is required for high levels of hPLP1 gene activity; (4) has a broader effect, both spatially and temporally, than originally projected with mPlp1.

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Section: Introductionmentioning

confidence: 99%

The wmN1 enhancer region in intron 1 is required for expression of human PLP1

Hamdan

Patyal

Kockara

et al. 2018

Glia

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“…The protein has been shown to recognize a target motif in the promoter of the human myelin PLP (proteolipid protein) gene ( PLP1 ) where it seemingly functions as a transcriptional activator (Berndt et al, 2001). PLP1/Plp1 gene expression is regulated in a spatiotemporal manner and, in oligodendrocytes, is responsible for nearly half the protein in CNS (central nervous system) myelin from adults (reviewed in Wight and Dobretsova, 2004). Categorization of YY1 as an activator of human PLP1 gene transcription stems from studies by Berndt et al showing that: (i) it binds selectively to a YY1 target site located within a region of the PLP1 promoter referred to as site 3 [positions −130 to −104 relative to the transcription start point (+1)] (Berndt et al, 2001), which previously had been shown to bind nuclear protein(s) in a sequence-specific manner (Berndt et al, 1992); (ii) deletion–transfection analysis in glial cells using various PLP1 promoter driven reporter constructs revealed a dramatic decrease in reporter gene activity when site 3 was deleted along with another, unrelated, protein binding site (site 2; positions −76 to −50) (Berndt et al, 1992); (iii) the level of expression of a PLP1 -reporter gene construct that contains PLP1 sequences from −1088 to +85 was increased when human (SVG) or rat (CG4) glial cell lines were co-transfected with a YY1 expression plasmid, but not with an analogous construct having a mutant site 3 that disrupts YY1 binding (Berndt et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…The structure of the gene in mouse and man is quite similar (reviewed in Wight and Dobretsova, 2004). The 5′-flanking DNA is highly conserved between the two species, demonstrating 50% identity for the proximal 1.3 kb of sequence and 91% identity among the initial 135 nucleotides using the algorithm of Myers and Miller (1988).…”

Section: Introductionmentioning

confidence: 99%

YY1 Negatively Regulates Mouse Myelin Proteolipid Protein (PLP1) Gene Expression in Oligodendroglial Cells

Zolova

Wight

2011

ASN Neuro

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YY1 (Yin and Yang 1) is a multifunctional, ubiquitously expressed, zinc finger protein that can act as a transcriptional activator, repressor, or initiator element binding protein. Previous studies have shown that YY1 modulates the activity of reporter genes driven by the myelin PLP (proteolipid protein) (PLP1/Plp1) promoter. However, it is known that Plp1 intron 1 DNA contains regulatory elements that are required for the dramatic increase in gene activity, coincident with the active myelination period of CNS (central nervous system) development. The intron in mouse contains multiple prospective YY1 target sites including one within a positive regulatory module called the ASE (anti-silencer/enhancer) element. Results presented here demonstrate that YY1 has a negative effect on the activity of a Plp1-lacZ fusion gene [PLP(+)Z] in an immature oligodendroglial cell line (Oli-neu) that is mediated through sequences present in Plp1 intron 1 DNA. Yet YY1 does not bind to its alleged site in the ASE (even though the protein is capable of recognizing a target site in the promoter), indicating that the down-regulation of PLP(+)Z activity by YY1 in Oli-neu cells does not occur through a direct interaction of YY1 with the ASE sequence. Previous studies with Yy1 conditional knockout mice have demonstrated that YY1 is essential for the differentiation of oligodendrocyte progenitors. Nevertheless, the current study suggests that YY1 functions as a repressor (not an activator) of Plp1 gene expression in immature oligodendrocytes. Perhaps YY1 functions to keep the levels of PLP in check in immature cells before vast quantities of the protein are needed in mature myelinating oligodendrocytes.

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“…However, in spite of being the most abundant protein in the CNS, myelin gene expression is regulated in a spatiotemporal manner with maximal levels of expression occurring in oligodendrocytes during the active myelination period of CNS development (Wight and Dobretsova, 2004). It has been documented through numerous studies in mouse models that overexpression or deficiency of one or more myelin component in the CNS can result in induction of compensatory protein clearance mechanisms such as increase in numbers of CD11b positive microglia, phagocytosis and subsequent autoimmune inflammation (Ip et al, 2008; Karim et al, 2007; Leder et al, 2007; Muller et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Myelin antigen load influences antigen presentation and severity of central nervous system autoimmunity

Jaini

Popescu

Flask

et al. 2013

Journal of Neuroimmunology

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This study was designed to understand the impact of self-antigen load on manifestation of organ specific autoimmunity. Using a transgenic mouse model characterized by CNS hypermyelination, we show that larger myelin content results in greater severity of experimental autoimmune encephalomyelitis attributable to an increased number of microglia within the hypermyelinated brain. We conclude that a larger self-antigen load affects an increase in number of tissue resident antigen presenting cells (APCs) most likely due to compensatory antigen clearance mechanisms thereby enhancing the probability of productive T cell-APC interactions in an antigen abundant environment and results in enhanced severity of autoimmune disease.

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Where, when and how much: regulation of myelin proteolipid protein gene expression

Cited by 27 publications

References 149 publications

The wmN1 enhancer region in intron 1 is required for expression of human PLP1

The wmN1 enhancer region in intron 1 is required for expression of human PLP1

YY1 Negatively Regulates Mouse Myelin Proteolipid Protein (PLP1) Gene Expression in Oligodendroglial Cells

Myelin antigen load influences antigen presentation and severity of central nervous system autoimmunity

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