Central nervous system myelination in mice with deficient expression of Notch1 receptor.
Activity of the Notch1 gene is known to inhibit oligodendrocyte (OL) differentiation in vitro. We tested the hypothesis that the Notch1 pathway regulates in vivo myelin formation, by examining brain myelination of Notch1 receptor null heterozygotes mutant animals (Notch1(+/-)). We show that a deficiency in Notch1 expression leads to increased abundance of products of specific myelin genes in myelinated areas of the brain during the first 2 weeks of postnatal life. We observed increased numbers of myelinated axons in optic nerves and the presence of myelinated fibers in the molecular layer (ML) of the Notch1(+/-) cerebella. These findings were accompanied by up-regulation of Mash1 and down-regulation of Hes5 proteins. In addition, we found expression of Jagged1, one of the Notch1 activators, in unmyelinated axons of the cerebellar ML during normal development. Our findings indicate that the Jagged/Notch signaling pathway might actively participate in the regulation of myelination during central nervous system development and suggest that certain neuronal populations might regulate whether their axons are myelinated by the expression of inhibitory signals such as Jagged1.
Givogri
Maria I
MI
Neurobiochemistry Group, Mental Retardation Research Center, School of Medicine, University of California, Los Angeles, California 90024, USA.
Costa
Rui M
RM
Schonmann
Vilma
V
Silva
Alcino J
AJ
Campagnoni
Anthony T
AT
Bongarzone
Ernesto R
ER
D000818:Animals; D001369:Axons / Q000378:metabolism / Q000648:ultrastructure; D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D002452:Cell Count; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology / Q000378:metabolism*; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D006579:Heterozygote; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D009186:Myelin Sheath / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism; D009900:Optic Nerve / Q000378:metabolism / Q000648:ultrastructure; D014176:Protein Biosynthesis; D011506:Proteins; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D012097:Repressor Proteins / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D011506:Proteins; D012333:RNA, Messenger; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D000072099:Serrate-Jagged Proteins; D014157:Transcription Factors; C499317:Ascl1 protein, mouse; C489685:Hes5 protein, mouse; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; C497762:Notch1 protein, mouse; C077478:HES5 protein, human