title: Multiple roles of Id4 in developmental myelination: predicted outcomes and unexpected findings.
abstract: Myelination in the central nervous system is a complex process requiring the integration of oligodendrocyte progenitor differentiation and the coordinate expression of myelin genes. This study addresses the role of the helix-loop-helix protein Id4 in these two events. Overexpression of Id4 in oligodendrocyte progenitors prevents differentiation and consequently decreases the endogenous expression of all myelin genes. Conversely, progenitors lacking Id4 display precocious differentiation both in vitro and in vivo, and this phenotype is partially compensated by increased apoptosis. Besides this role, Id4 also has the ability to decrease the activity of specific myelin promoters, since Id4 overexpression decreases the activity of luciferase reporter genes driven by the ceramide galactosyltransferase (CGT) or myelin basic protein (MBP) promoter, but not by a myelin proteolipid protein (PLP) promoter. Consistent with these results, the expression levels of MBP and CGT are greater in neonatal Id4 null mice when compared with wild-type siblings and correlate with the early detection of MBP immunoreactive myelinated fibers. In contrast, the levels of other myelin proteins, such as PLP and myelin associated glycoprotein (MAG) are decreased in the Id4 null mice. MAG expression is localized to the soma rather than the fibers of immunoreactive cells in the neonatal brain and compensated at later developmental stages. These data support the role of Id4 as oligodendrocyte differentiation inhibitor with the ability to differentially regulate the expression and subcellular distribution of myelin gene products.
authors.affiliation: Department of Neuroscience and Cell Biology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.
authors.forename: Mireya
authors.initials: M
authors.lastname: Marin-Husstege
authors.forename: Ye
authors.initials: Y
authors.lastname: He
authors.forename: Jiadong
authors.initials: J
authors.lastname: Li
authors.forename: Toru
authors.initials: T
authors.lastname: Kondo
authors.forename: Fred
authors.initials: F
authors.lastname: Sablitzky
authors.forename: Patrizia
authors.initials: P
authors.lastname: Casaccia-Bonnefil
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D002478:Cells, Cultured; D003720:Densitometry; D015870:Gene Expression; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051796:Inhibitor of Differentiation Proteins / Q000502:physiology*; D008156:Luciferases / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008934:Mitogens / Q000494:pharmacology; D004676:Myelin Basic Protein / Q000235:genetics / Q000502:physiology; D009186:Myelin Sheath / Q000235:genetics* / Q000502:physiology*; D009836:Oligodendroglia / Q000502:physiology; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000502:physiology; D013963:Thyroid Hormones / Q000494:pharmacology; D014162:Transfection
chemical_list: C086479:Idb4 protein, mouse; D051796:Inhibitor of Differentiation Proteins; D008934:Mitogens; D004676:Myelin Basic Protein; D013963:Thyroid Hormones; D008156:Luciferases