Regulation of the myelin gene periaxin provides evidence for Krox-20-independent myelin-related signalling in Schwann cells

Parkinson, David B.; Dickinson, Sarah; Bhaskaran, A; Kinsella, Matthew; Brophy, Peter; Sherman, Diane L.; Sharghi-Namini, Soheila; Alonso, Maria B Duran; Mirsky, Rhona; Jessen, Kristján R.

doi:10.1016/s1044-7431(03)00024-1

Cited by 48 publications

(66 citation statements)

References 46 publications

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“…Here, we show that Krox-20 plays a direct role in MBP regulation. However, in our 135 bp construct, no obvious binding site for Krox-20 was found, suggesting that Krox-20 is not crucial but rather, as seen for the periaxin gene (Parkinson et al, 2003), is used to amplify the activity of the enhancer. These combined results suggest that Krox-20 plays an important role in late myelin gene expression.…”

Section: Discussionmentioning

confidence: 71%

Functional Organization of a Schwann Cell Enhancer

Denarier

Forghani²,

Farhadi³

et al. 2005

J. Neurosci.

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Myelin basic protein (MBP) gene expression is conferred in oligodendrocytes and Schwann cells by different upstream enhancers. InSchwann cells, expression is controlled by a 422 bp enhancer lying Ϫ9 kb from the gene. We show here that it contains 22 mammalian conserved motifs Ն6 bp. To investigate their functional significance, different combinations of wild-type or mutated motifs were introduced into reporter constructs that were inserted in single copy at a common hypoxanthine phosphoribosyltransferase docking site in embryonic stem cells. Lines of transgenic mice were derived, and the subsequent qualitative and quantitative expression phenotypes were compared at different stages of maturation. In the enhancer core, seven contiguous motifs cooperate to confer Schwann cell specificity while different combinations of flanking motifs engage, at different stages of Schwann cell maturation, to modulate expression level. Mutation of a Krox-20 binding site reduces the level of reporter expression, whereas mutation of a potential Sox element silences reporter expression. This potential Sox motif was also found conserved in other Schwann cell enhancers, suggesting that it contributes widely to regulatory function. These results demonstrate a close relationship between phylogenetic footprints and regulatory function and suggest a general model of enhancer organization. Finally, this investigation demonstrates that in vivo functional analysis, supported by controlled transgenesis, can be a robust complement to molecular and bioinformatics approaches to regulatory mechanisms.

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Section: Discussionmentioning

confidence: 71%

Functional Organization of a Schwann Cell Enhancer

Denarier

Forghani²,

Farhadi³

et al. 2005

J. Neurosci.

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“…Previous work on periaxin regulation indicates that Egr2 acts as an amplifier of pre-existing myelin gene expression because there is a reduced, but significant, level of periaxin induction even in the absence of Egr2/Krox20 (also Mpz and Mag) (Parkinson et al, 2003). Moreover, expression of periaxin temporally precedes Egr2 induction in developing Schwann cells, which indicates that there is an Egr2-independent mode of periaxin induction.…”

Section: Discussionmentioning

confidence: 92%

“…The importance of these sequences to periaxin regulation has not been established, but it is likely that elements downstream of the promoter are involved because constructs containing up to 12 kb of upstream sequence do not respond to either Egr2 expression or cAMP induction (Parkinson et al, 2003). If the intronassociated site is functional, it is possible that intron-associated enhancers are a common theme in myelin gene regulation because binding of Egr2 and Sox10 to conserved sites has also been detected in introns of the Mag and Mpz genes LeBlanc et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…As a preliminary analysis of these sites, ChIP assays were performed to test binding of Egr2 to two of the novel candidate sites in both the S16 Schwann cell line (Hai et al, 2002), and in freshly dissected sciatic nerves of rat pups (postnatal day 15). The site in the periaxin gene (located within the first intron, ~4.5 kb downstream of the transcription start site) was chosen because its expression depends on Egr2 (Parkinson et al, 2003) and is developmentally regulated in a manner similar to the Mpz gene (Gillespie et al, 1994). In addition, the Mag upstream site was chosen because our previous work has detected binding of Egr2 to the intronassociated site at +1552 LeBlanc et al, 2007).…”

Section: Identification Of Evolutionarily Conserved Sox/egr2 Binding mentioning

confidence: 99%

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Interactions of Sox10 and Egr2 in myelin gene regulation

et al. 2007

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Myelination in the PNS is accompanied by a large induction of the Myelin Protein Zero (Mpz) gene to produce the most abundant component in peripheral myelin. Analyses of knockout mice have shown that the EGR2/Krox20 and SOX10 transcription factors are required for Mpz expression. Our recent work has shown that the dominant EGR2 mutations associated with human peripheral neuropathies cause disruption of EGR2/SOX10 synergy at specific sites, including a conserved enhancer element in the first intron of the Mpz gene. Further investigation of Egr2/Sox10 interactions reveals that activation of the Mpz intron element by Egr2 requires both Sox10-binding sites. In addition, both Egr1 and Egr3 cooperate with Sox10 to activate this element, which indicates that this capacity is conserved among Egr family members. Finally, a conserved composite structure of Egr2/ Sox10-binding sites in the genes encoding Mpz, Myelin-associated glycoprotein (Mag), and Myelin Basic Protein (Mbp) genes was used to screen for similar modules in other myelin genes, revealing a potential regulatory element in the periaxin gene. Overall, these results elucidate a working model for developmental regulation of Mpz expression, several facets of which extend to regulation of other peripheral myelin genes.

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“…RNA isolation, reverse transcriptase reaction, and reverse transcription (RT)-PCR experiments were performed as described previously (D'Antonio et al, 2006). Primers for periaxin were as described by Parkinson et al (2003). Primers for P 0 were as follows: P 0 sense, 5Ј-GTCCAGTGAATGGGTCTCAG-3Ј; P 0 antisense (AS), 5Ј-GCTCCCAACAACACCCCATA-3Ј.…”

Section: Generation Of P0 Cre/t␤riimentioning

confidence: 99%

TGFβ Type II Receptor Signaling Controls Schwann Cell Death and Proliferation in Developing Nerves

et al. 2006

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During development, Schwann cell numbers are precisely adjusted to match the number of axons. It is essentially unknown which growth factors or receptors carry out this important control in vivo. Here, we tested whether the type II transforming growth factor (TGF) ␤ receptor has a role in this process. We generated a conditional knock-out mouse in which the type II TGF␤ receptor is specifically ablated only in Schwann cells. Inactivation of the receptor, evident at least from embryonic day 18, resulted in suppressed Schwann cell death in normally developing and injured nerves. Notably, the mutants also showed a strong reduction in Schwann cell proliferation. Consequently, Schwann cell numbers in wild-type and mutant nerves remained similar. Lack of TGF␤ signaling did not appear to affect other processes in which TGF␤ had been implicated previously, including myelination and response of adult nerves to injury. This is the first in vivo evidence for a growth factor receptor involved in promoting Schwann cell division during development and the first genetic evidence for a receptor that controls normal developmental Schwann cell death.

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Regulation of the myelin gene periaxin provides evidence for Krox-20-independent myelin-related signalling in Schwann cells

Cited by 48 publications

References 46 publications

Functional Organization of a Schwann Cell Enhancer

Functional Organization of a Schwann Cell Enhancer

Interactions of Sox10 and Egr2 in myelin gene regulation

TGFβ Type II Receptor Signaling Controls Schwann Cell Death and Proliferation in Developing Nerves

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