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Adult CNP::EGFP transgenic mouse shows pronounced hypomyelination and an increased vulnerability to cuprizone-induced demyelination.
Exp Neurol. 2012 Jan; 233(1):490-504.EN

Abstract

CNP::EGFP transgenic mice, genetically engineered to express the enhanced green fluorescent protein (EGFP) under the control of the 2-3-cyclic nucleotide 3-phosphodiesterase (CNPase) promoter in oligodendroglial and Schwann cells, constitute a very important and widely used tool for the study of oligodendrocyte (OLG) development and function in young mice. Our results showed that CNP::EGFP mice were significantly more susceptible to CPZ-induced demyelination, as evaluated by MBP immunostaining, oligodendroglial progenitor cell (OPC) recruitment and astroglial, microglial and nestin response. This enhanced vulnerability was a consequence of their hypomyelination. CNP::EGFP control mice also displayed a significant decrease in corpus callosum (CC) thickness and MBP immunoreactivity. Morphometric analysis further showed a significant decrease in the frequency of myelinated axons, myelin turns (lamellae) and g-ratio carried out in the optic nerve (ON) and CC of CNP::EGFP, as compared to WT mice. Moreover, our results showed a decrease in the number of axons of small caliber, concomitantly with an increase in the number of axons of bigger size with more and enlarged mitochondria, which suggests a high energy demand. These findings and those displaying that MBP+ cells and NF200 staining in the CNP::EGFP cortex were more sparsely distributed provide evidence of axonal loss, which was supported by a decreased number of NeuN+ cells in the CA3 fields of the hippocampus. Transgenic mice also showed an increase in microglial and astroglial activation, accompanied by enhanced lipid peroxidation and recruitment of morphologically altered OPC. Finally, CNPase protein levels proved to be lower than MBP in the CC, which might indicate an altered pattern in myelin proteins with a CNPase deficiency. Behavioral analysis of adult CNP::EGFP transgenic mice supported our results, as it revealed a decrease in locomotion, exploratory activity and motor impairment, as compared to their WT littermates. Our data highlight the relevance of confronting results obtained in adult CNP::EGFP mice with those observed in WT mice. According to our findings, CNP::EGFP hypomyelination might be triggered by the cellular stress induced by the high level of EGFP expression in mature OLG. Adult CNP::EGFP mice could be considered a useful tool to evaluate future therapies for demyelinating diseases such as multiple sclerosis (MS), since these animals present chronic demyelination with axonal degeneration, a characteristic of such pathologies.

Authors+Show Affiliations

Dept of Biological Chemistry, IQUIFIB, FFyB, UBA-CONICET, Bs As, Argentina.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22155618

Citation

Millet, V, et al. "Adult CNP::EGFP Transgenic Mouse Shows Pronounced Hypomyelination and an Increased Vulnerability to Cuprizone-induced Demyelination." Experimental Neurology, vol. 233, no. 1, 2012, pp. 490-504.
Millet V, Marder M, Pasquini LA. Adult CNP::EGFP transgenic mouse shows pronounced hypomyelination and an increased vulnerability to cuprizone-induced demyelination. Exp Neurol. 2012;233(1):490-504.
Millet, V., Marder, M., & Pasquini, L. A. (2012). Adult CNP::EGFP transgenic mouse shows pronounced hypomyelination and an increased vulnerability to cuprizone-induced demyelination. Experimental Neurology, 233(1), 490-504. https://doi.org/10.1016/j.expneurol.2011.11.028
Millet V, Marder M, Pasquini LA. Adult CNP::EGFP Transgenic Mouse Shows Pronounced Hypomyelination and an Increased Vulnerability to Cuprizone-induced Demyelination. Exp Neurol. 2012;233(1):490-504. PubMed PMID: 22155618.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Adult CNP::EGFP transgenic mouse shows pronounced hypomyelination and an increased vulnerability to cuprizone-induced demyelination. AU - Millet,V, AU - Marder,M, AU - Pasquini,L A, Y1 - 2011/12/01/ PY - 2011/07/18/received PY - 2011/10/17/revised PY - 2011/11/21/accepted PY - 2011/12/14/entrez PY - 2011/12/14/pubmed PY - 2012/3/27/medline SP - 490 EP - 504 JF - Experimental neurology JO - Exp Neurol VL - 233 IS - 1 N2 - CNP::EGFP transgenic mice, genetically engineered to express the enhanced green fluorescent protein (EGFP) under the control of the 2-3-cyclic nucleotide 3-phosphodiesterase (CNPase) promoter in oligodendroglial and Schwann cells, constitute a very important and widely used tool for the study of oligodendrocyte (OLG) development and function in young mice. Our results showed that CNP::EGFP mice were significantly more susceptible to CPZ-induced demyelination, as evaluated by MBP immunostaining, oligodendroglial progenitor cell (OPC) recruitment and astroglial, microglial and nestin response. This enhanced vulnerability was a consequence of their hypomyelination. CNP::EGFP control mice also displayed a significant decrease in corpus callosum (CC) thickness and MBP immunoreactivity. Morphometric analysis further showed a significant decrease in the frequency of myelinated axons, myelin turns (lamellae) and g-ratio carried out in the optic nerve (ON) and CC of CNP::EGFP, as compared to WT mice. Moreover, our results showed a decrease in the number of axons of small caliber, concomitantly with an increase in the number of axons of bigger size with more and enlarged mitochondria, which suggests a high energy demand. These findings and those displaying that MBP+ cells and NF200 staining in the CNP::EGFP cortex were more sparsely distributed provide evidence of axonal loss, which was supported by a decreased number of NeuN+ cells in the CA3 fields of the hippocampus. Transgenic mice also showed an increase in microglial and astroglial activation, accompanied by enhanced lipid peroxidation and recruitment of morphologically altered OPC. Finally, CNPase protein levels proved to be lower than MBP in the CC, which might indicate an altered pattern in myelin proteins with a CNPase deficiency. Behavioral analysis of adult CNP::EGFP transgenic mice supported our results, as it revealed a decrease in locomotion, exploratory activity and motor impairment, as compared to their WT littermates. Our data highlight the relevance of confronting results obtained in adult CNP::EGFP mice with those observed in WT mice. According to our findings, CNP::EGFP hypomyelination might be triggered by the cellular stress induced by the high level of EGFP expression in mature OLG. Adult CNP::EGFP mice could be considered a useful tool to evaluate future therapies for demyelinating diseases such as multiple sclerosis (MS), since these animals present chronic demyelination with axonal degeneration, a characteristic of such pathologies. SN - 1090-2430 UR - https://www.unboundmedicine.com/medline/citation/22155618/Adult_CNP::EGFP_transgenic_mouse_shows_pronounced_hypomyelination_and_an_increased_vulnerability_to_cuprizone_induced_demyelination_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-4886(11)00432-8 DB - PRIME DP - Unbound Medicine ER -