Multiple roles of Id4 in developmental myelination: Predicted outcomes and unexpected findings

Marin-Husstege, Mireya; He, Ye; Li, Jiadong; Kondo, Toru; Sablitzky, Fred; Casaccia‐Bonnefil, Patrizia

doi:10.1002/glia.20385

Cited by 76 publications

(80 citation statements)

References 42 publications

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“…Of the NAB-regulated genes selected by these criteria ( (33)(34)(35)(36). Schwann cells express all members of the Id family, but Id2 and Id4 levels decline during the course of myelination and are expressed at relatively low levels in mature nerve (26,37,38).…”

Section: Resultsmentioning

confidence: 99%

Active Gene Repression by the Egr2·NAB Complex during Peripheral Nerve Myelination

Mager

Ward

Srinivasan

et al. 2008

Journal of Biological Chemistry

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The Egr2/Krox20 transactivator is required for activation of many myelin-associated genes during peripheral nerve myelination by Schwann cells. However, recent work has indicated that Egr2 not only activates genes required for peripheral nerve myelination but may also be involved in gene repression. The NAB (NGFI-A/Egr-binding) corepressors interact with Egr2 and are required for proper coordination of myelin formation. Therefore, NAB proteins could mediate repression of some Egr2 target genes, although direct repression by Egr2 or NAB proteins during myelination has not been demonstrated. To define the physiological role of NAB corepression in gene repression by Egr2, we tested whether the Egr2⅐NAB complex directly repressed specific target genes. A screen for NAB-regulated genes identified several (including Id2, Id4, and Rad) that declined during the course of peripheral nerve myelination. In vivo chromatin immunoprecipitation analysis of the myelinating sciatic nerve was used to show developmental association of both Egr2 and NAB2 on the Id2, Id4, and Rad promoters as they were repressed during the myelination process. In addition, NAB2 represses transcription by interaction with the chromodomain helicase DNA-binding protein 4 (CHD4) subunit of the nucleosome remodeling and deacetylase chromatin remodeling complex, and we demonstrate that CHD4 occupies NAB-repressed promoters in a developmentally regulated manner in vivo. These results illustrate a novel aspect of genetic regulation of peripheral nerve myelination by showing that Egr2 directly represses genes during myelination in conjunction with NAB corepressors. Furthermore, repression of Id2 was found to augment activation of Mpz (myelin protein zero) expression.The early growth response-2 (Egr2/Krox20) 3 transcriptional activator is critically required for peripheral nerve myelination by Schwann cells. Peripheral nerve from Egr2/Krox20-deficient mice is characterized by arrested myelination and decreased myelin protein levels (1, 2), and recent analysis has indicated that Egr2/Krox20 is required for maintenance of peripheral myelin (3). In addition, mutations in EGR2 have been identified in several patients with myelin disorders such as CharcotMarie-Tooth (CMT) disease, Dejerine-Sottas syndrome, and congenital hypomyelinating neuropathy (4 -6) (reviewed in Ref. 7). Egr2 is induced in Schwann cells at the onset of myelination (1, 8) and is required for activation of a variety of genes involved in peripheral nerve myelination in vivo including Mpz (myelin protein zero) and Pmp22 (peripheral myelin protein-22), as well as genes involved in lipid biosynthesis (1, 2, 9). Recent work has demonstrated sites of Egr2 occupancy within activated myelin genes in vivo (10, 11).One of the EGR2 mutations associated with a very severe congenital hypomyelinating neuropathy (I268N (4)) prevents binding of EGR2 to NGFI-A/Egr-binding (NAB1 and NAB2) corepressors (12), which repress Egr-mediated transcription (13-15). The importance of NAB corepressors to the regulation of ...

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Section: Resultsmentioning

confidence: 99%

Active Gene Repression by the Egr2·NAB Complex during Peripheral Nerve Myelination

Mager

Ward

Srinivasan

et al. 2008

Journal of Biological Chemistry

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“…He also showed that overexpression of Id4 prolongs OPC proliferation and inhibits differentiation in the presence of PDGF and TH. Toru then collaborated with Fred Sablitzky at Nottingham University to show that neural stem cells isolated from the brains of Id4-deficient mouse embryos produce oligodendrocytes prematurely in culture (Marin-Husstege et al 2006). Taken together, these findings suggest that Id4 is another component of the timer and that its progressive decrease helps control when OPCs stop dividing and differentiate.…”

Section: Some Protein Components Of the Intracellular Timermentioning

confidence: 95%

Intracellular Developmental Timers

Raff¹

2007

Cold Spring Harbor Symposia on Quantitative Biology

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INTRODUCTIONOur interest in developmental timing began with a surprising experimental result obtained by Erika Abney, an immunologist who joined our group in the late 1970s. We had earlier defined a set of cell-type-specific markers that allowed us to distinguish the major types of glial cells found in suspensions and cultures of rat central nervous system (CNS) cells: astrocytes, which are heterogeneous and have many functions; oligodendrocytes, which myelinate neuronal axons; and ependymal cells, which line the fluid-filled ventricles of the brain (Raff et al. 1979). Analyzing cell suspensions prepared from developing rat brains from embryonic day eleven (E11) through to birth at approximately E21, she determined when the differentiated cells of each type first appeared. She found that the first astrocytes appeared at E15-E16, the first ependymal cells at E17-E18, and the first oligodendrocytes at around the time of birth (E21-E22). Each cell type always first appeared in very small numbers and rapidly increased over the following days. Remarkably, when she isolated cells from E10 brain and cultured them in 10% fetal calf serum (FCS), the times of first appearance of these three cell types were the same as if the cells had been left in the developing brain; moreover, when cultures were prepared from E13 brain, all three cell types first appeared 3 days earlier, just as in vivo (Abney et al. 1981). These results are as surprising today as they were when we published them more than 25 years ago, because the axial cues and morphogen gradients that play such an important part in controlling cell specification in early animal development are presumably missing in these cultures. Moreover, it seems unlikely that the sequential cell-cell interactions that are thought to help time events in development could occur normally in such cultures.Whatever the nature of the timing mechanisms involved, the finding that they apparently could operate normally in dissociated-cell culture over a 10-day period encouraged us to study them. The complexity of the brain cell cultures, however, was daunting, and so we turned to the developing optic nerve, which is much simpler, and we focused on the timing of oligodendrocyte development. AN INTRACELLULAR TIMER IN OLIGODENDROCYTE PRECURSOR CELLSThe optic nerve contains no neurons, although it contains the axons of retinal ganglion neurons. The main cell types in the nerve are astrocytes and oligodendrocytes, with smaller numbers of macrophages (microglia), blood vessel cells, and glial precursor cells. Whereas the astrocytes in the optic nerve develop from the neuroepithelial cells of the optic stalk (the primordium of the nerve), the oligodendrocytes develop from precursor cells that migrate into the developing nerve from the brain, beginning before birth (Small et al. 1987). The oligodendrocyte precursor cells (OPCs) divide a limited number of times before they stop and terminally differentiate into postmitotic oligodendrocytes. As in the brain, the first oligodendrocytes appear in the...

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“…Furthermore, it has been shown that only Id2, and not the other members of the family, Id1 and Id3, is able to abrogate the antiproliferative effects of tumor suppressor proteins of the retinoblastoma family allowing cell-cycle progression by physically interactions with them, (Lasorella et al, 2000). Finally it is known that Id4 has an essential role in the maturation of oligodendrocytes during development, thus progenitors lacking Id4 precociously maturate (Marin-Husstege et al, 2006). In summary Id factors can work as important regulators of different biological processes and they are commonly associated to maintenance of undifferentiated state and the mitotic activity of cells, being often downregulated when cells differentiate (Lyden et al, 1999, Shimizu-Nishikawa et al, 1999Ruzinova andBenezra, 2003, Sikder et al, 2003;Iavarone and Lasorella, 2006).…”

Section: Arrows) (F)mentioning

confidence: 99%

Expression of Id2 in the developing limb is associated with zones of active BMP signaling and marks the regions of growth and differentiation of the developing digits

Lorda‐Diez

Torre-Pérez²,

García‐Porrero³

et al. 2009

Int. J. Dev. Biol.

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Multiple roles of Id4 in developmental myelination: Predicted outcomes and unexpected findings

Cited by 76 publications

References 42 publications

Active Gene Repression by the Egr2·NAB Complex during Peripheral Nerve Myelination

Active Gene Repression by the Egr2·NAB Complex during Peripheral Nerve Myelination

Intracellular Developmental Timers

Expression of Id2 in the developing limb is associated with zones of active BMP signaling and marks the regions of growth and differentiation of the developing digits

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