The Proteolipid Protein Promoter Drives Expression outside of the Oligodendrocyte Lineage during Embryonic and Early Postnatal Development

Michalski, John-Paul; Anderson, Carrie L.; Beauvais, Ariane; Repentigny, Yves De; Kothary, Rashmi

doi:10.1371/journal.pone.0019772

Cited by 41 publications

(36 citation statements)

References 35 publications

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“…To examine whether mutant Htt is expressed in oligodendrocytes at the endogenous level, we crossed HD 140CAG knock-in (KI) mice with transgenic mice that selectively express GFP in oligodendrocytes under the control of the proteolipid protein ( PLP ) gene promoter (Mallon et al, 2002), which drives transgene expression predominantly in oligodendrocytes in adult mouse brain (Michalski et al, 2011). The crossed mice would thus allow us to define whether full-length mutant Htt is expressed in GFP-positive oligodendrocytes.…”

Section: Resultsmentioning

confidence: 99%

Mutant Huntingtin Downregulates Myelin Regulatory Factor-Mediated Myelin Gene Expression and Affects Mature Oligodendrocytes

Huang

Wei

Wang

et al. 2015

Neuron

150

149

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SUMMARY Growing evidence indicates that non-neuronal mutant huntingtin toxicity plays an important role in Huntington’s disease (HD); however, whether and how mutant huntingtin affects oligodendrocytes, which are vitally important for neural function and axonal integrity, remain unclear. We first verified the presence of mutant huntingtin in oligodendrocytes in HD140Q knock-in mice. We then established transgenic mice (PLP-150Q) that selectively express mutant huntingtin in oligodendrocytes. PLP-150Q mice show progressive neurological symptoms and early death, as well as age-dependent demyelination and reduced expression of myelin genes that are downstream of myelin regulatory factor (MYRF or MRF), a transcriptional regulator that specifically activates and maintains the expression of myelin genes in mature oligodendrocytes. Consistently, mutant huntingtin binds abnormally to MYRF and affects its transcription activity. Our findings suggest that dysfunction of mature oligodendrocytes is involved in HD pathogenesis and may also make a good therapeutic target.

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Section: Resultsmentioning

confidence: 99%

Mutant Huntingtin Downregulates Myelin Regulatory Factor-Mediated Myelin Gene Expression and Affects Mature Oligodendrocytes

Huang

Wei

Wang

et al. 2015

Neuron

150

149

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“…Conditional expression of DTau was obtained by using the PLPERT mouse line [45], which has been widely used with consistent high-efficiency recombination [46,53,54]. It is known that PLP is exclusively expressed in mature OLGs; however, adult CNS is known to contain a population of NG2 cells that express PLP [55].…”

Section: Discussionmentioning

confidence: 99%

“…It is known that PLP is exclusively expressed in mature OLGs; however, adult CNS is known to contain a population of NG2 cells that express PLP [55]. Michalski et al [46] showed that PLP promoter-driven expression occurs in NG2 cells and progressively diminishes from 20 to 5…”

Section: Discussionmentioning

confidence: 99%

“…1b), respectively. To induce expression of EGFP-DTau exclusively in OLGs, PLP/ CreERT: Floxed STOP-LacZ/EGFP-DTau TG mice were obtained by crossing Floxed LacZ-STOP/EGFP-DTau mice with a TM-inducible Cre driver line that regulates Cre under the control of PLP promoter [45,46]. Myelin PLP is the major myelin protein in the CNS.…”

Section: Generation Of Floxed Lacz-stop/egfp-dtau Founder Tg Micementioning

confidence: 99%

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Inducible Expression of a Truncated Form of Tau in Oligodendrocytes Elicits Gait Abnormalities and a Decrease in Myelin: Implications for Selective CNS Degenerative Diseases

LoPresti

2015

Neurochem Res

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The cytoskeleton protein Tau present in oligodendrocytes (OLGs) promotes cellular process outgrowth and myelination; whereas abnormally hyperphosphorylated Tau has been shown to be present in the most debilitating form of multiple sclerosis and in selective dementias. This research examined the functional consequences of expressing a truncated form of Tau in OLGs during the second postnatal life. In particular, this truncated form of Tau (∆Tau) retains the Fyn-binding domain but lacks the microtubule-binding domain. Similar to hyperphosphorylated Tau, ∆Tau cannot bind the cytoskeleton and is missorted. The Cre/loxP recombination system was used to generate transgenic (TG) founder lines, which contain a Floxed LacZ-STOP cassette to prevent expression of enhanced green fluorescence protein (EGFP)-∆Tau. The founder lines were then crossed with a Tamoxifen (TM)-inducible proteolipid protein (PLP)-dependent Cre driver line. Myelin PLP is the major myelin protein in the central nervous system (CNS). TM was given at postnatal day (p) 12 for 3 days, and CNS tissues were collected at p22. Only TG mice with both EGFP-∆Tau and Cre manifested an overt phenotype of loss of balance and stumbles starting around p18. CNS tissues obtained from TM-treated EGFP-∆Tau/Cre double transgenic mice had recombined PCR products, GFP, and diminished brain myelin. GFP was expressed in OLGs, but not in neurons or astrocytes. On the contrary, TM-treated TG mice with only one of the two transgenes, i.e., Cre or Tau, did not have recombinant PCR products, GFP, diminished myelin, or abnormal phenotype. Thus, this inducible model shows for the first time that a non-microtubule-associated Tau protein in OLGs elicits both myelin decrease and gait abnormalities, similar to the occurrence in selective demyelinating and neurodegenerative diseases.

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“…OPCs express specific antigens such as platelet-derived growth factor alpha receptor (PDGFaR) and chondroitin sulfate proteoglycan NG2 (Stallcup and Beasley 1987;Nishiyama et al 1996;Butt et al 1999). Recent studies have shown that OPCs can be selectively detected in transgenic mice encoding a reporter gene driven by specific promoters including proteolipid protein (PLP) (Mallon et al 2002;Michalski et al 2011), PDGFaR (Rivers et al 2008;Boda et al 2015), and NG2 (Zhu et al 2008;Komitova et al 2011). While PLP gene shows many splicing variants in mice and humans (Bongarzone et al 1999;Li et al 2009;Sarret et al 2010), only PLP and DM-20 mRNA transcripts were identified as splicing variants encoded by PLP gene in rats (Sarret et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Regulation of DM-20 mRNA expression and intracellular translocation of glutathione-S-transferase pi isoform during oligodendrocyte differentiation in the adult rat spinal cord

Kitada

Takeda

Dezawa

2016

Histochem Cell Biol

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We previously demonstrated that NG2-positive oligodendrocyte precursor cells (OPCs) do not express DM-20 mRNA and identified a distinct DM-20 mRNA-positive cell population expressing glutathione-S-transferase pi isoform (GST-pi) in the nucleus (GST-pi(Nuc)) of the adult rat spinal cord. As GST-pi intranuclear localization correlates with progenitor cell properties, we examined the differentiation status of this cell population under the intensive 5-bromo-2'-deoxyuridine (BrdU) administration method, consisting of intraperitoneal BrdU injections every 2 h for 48 h. We observed that a certain population of proliferating/proliferated cells expressed DM-20 mRNA, and sometimes two proliferating/proliferated cells were observed still attached to each other. We performed triple staining for BrdU, DM-20 mRNA, and NG2 and found pairs of neighboring BrdU-positive cells, which were considered to originate from the same progenitor cells and where both cells expressed DM-20 mRNA. Triple staining for BrdU, DM-20 mRNA, and GST-pi detected proliferating/proliferated cells exhibiting the GST-pi(Nuc)/DM-20 mRNA-positive expression pattern. These findings suggested the presence of a GST-pi(Nuc)/DM-20 mRNA-positive oligodendrocyte-lineage progenitor cell population in the adult rat spinal cord. However, we did not find any pair of neighboring BrdU-positive cells with this expression pattern. These observations collectively support the idea that GST-pi(Nuc)/DM-20 mRNA-expressing cells are the progeny of NG2-positive OPCs rather than a novel type of oligodendrocyte-lineage progenitor cells and that DM-20 mRNA expression is dynamically regulated during differentiation of OPCs into oligodendrocytes.

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The Proteolipid Protein Promoter Drives Expression outside of the Oligodendrocyte Lineage during Embryonic and Early Postnatal Development

Cited by 41 publications

References 35 publications

Mutant Huntingtin Downregulates Myelin Regulatory Factor-Mediated Myelin Gene Expression and Affects Mature Oligodendrocytes

Mutant Huntingtin Downregulates Myelin Regulatory Factor-Mediated Myelin Gene Expression and Affects Mature Oligodendrocytes

Inducible Expression of a Truncated Form of Tau in Oligodendrocytes Elicits Gait Abnormalities and a Decrease in Myelin: Implications for Selective CNS Degenerative Diseases

Regulation of DM-20 mRNA expression and intracellular translocation of glutathione-S-transferase pi isoform during oligodendrocyte differentiation in the adult rat spinal cord

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