The D355V Mutation Decreases EGR2 Binding To An Element Within The CX32 Promoter

Musso, Marco; Balestra, P; Bellone, Emilia; Cassandrini, Denise; Maria, Emilio Di; D’Oria, Luisa; Grandis, Marina; Mancardi, G. L.; Schenone, Angelo; Levi, Giovanni; Ajmar, Franco; Mandich, Paola

doi:10.1046/j.1529-8027.2001.01007-37.x

Cited by 8 publications

(13 citation statements)

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“…Schwann cells arrest in a premyelinating state in Krox-20 knock-out mice, and a direct role for Krox-20 in the regulation of connexin-32 has been shown previously (Musso et al, 2001). Here, we show that Krox-20 plays a direct role in MBP regulation.…”

Section: Discussionsupporting

confidence: 80%

“…Thus, differentiation of the Schwann cell lineage is controlled through a regulatory network of transcription factors acting at multiple stages of Schwann cell maturation. Evidence from in vitro studies suggests that these same factors may regulate individual myelin genes at later stages of maturation (Peirano et al, 2000;Musso et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Functional Organization of a Schwann Cell Enhancer

Denarier

Forghani²,

Farhadi³

et al. 2005

J. Neurosci.

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“…Krox20 has been proposed to directly control the transcription of several genes expressed in Schwann cells (Zorick et al, 1999;Bondurand et al, 2001;Musso et al, 2001;Taveggia et al, 2004;LeBlanc et al, 2006). The fact that we observe modifications in gene expression in Krox20 I268F/I268F mutants both for upregulated and downregulated genes suggests that Nab proteins may cooperate with Krox20 for both activation and repression of its targets.…”

Section: Molecular Functions Of the Nab Factorsmentioning

confidence: 50%

“…Krox20 is absolutely required for the progression of promyelinating Schwann cells into myelination and for the expression of most myelin-specific genes (Topilko et al, 1994;Le et al, 2005a). Additional evidence suggest that Krox20 constitutes a master regulator of the myelination process, because its forced expression results in an arrest in cell proliferation (Parkinson et al, 2004) and in the induction of genes encoding structural myelin proteins and enzymes involved in lipid synthesis (Nagarajan et al, 2001;Le et al, 2005a), presumably as a result of direct transcriptional activation (Bondurand et al, 2001;Musso et al, 2001;Taveggia et al, 2004;LeBlanc et al, 2005LeBlanc et al, , 2006.…”

Section: Introductionmentioning

confidence: 99%

Disruption of Krox20-Nab Interaction in the Mouse Leads to Peripheral Neuropathy with Biphasic Evolution

Desmazières¹,

Decker²,

Vallat³

et al. 2008

Journal of Neuroscience

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Krox20/Egr2 is a zinc finger transcription factor that plays essential roles in several developmental processes, including peripheral nervous system myelination by Schwann cells, where it acts as a master gene regulator. Krox20 is known to interact with cofactors of the Nab family and a mutation affecting isoleucine 268, which prevents this interaction, has been shown to result in congenital hypomyelinating neuropathy in humans. To further investigate the role of this interaction, we have introduced such a mutation, Krox20 I268F, in the mouse germ line. Clinical, immunohistochemical, and ultrastructural analyses of the homozygous mutants reveal that they develop a severe hypomyelination phenotype that mimics the human syndrome. Furthermore, a time-course analysis of the disease indicates that it follows a biphasic evolution, the hypomyelination phase being followed by a dramatic demyelination. Although for the regulation of most analyzed Krox20 target genes the mutation behaves as a loss of function, this is not the case for a few of them. This differential effect indicates that the molecular function of the Krox20 -Nab interaction is target dependent and might explain the degradation of the residual myelin, because of imbalances in its composition. In conclusion, this work provides a novel and useful model for severe human peripheral neuropathies.

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“…Mutations in SOX10 are associated with a complex syndrome involving peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome and Hirschsprung disease (Inoue et al, 2004). Dominant, neuropathy-associated mutations in EGR2 have been identified in all three zinc fingers of the DNA-binding domain (Warner et al, 1998;Bellone et al, 1999;Timmerman et al, 1999;Pareyson et al, 2000;Mikesova et al, 2005), and these mutations generally either impair or prevent DNA-binding Musso et al, 2001;Musso et al, 2003). Dominant mutants of EGR2 exert a dominant-negative effect on the activation of some endogenous target genes in Schwann cells by wild type EGR2 (Nagarajan et al, 2001;ArthurFarraj et al, 2006), with the most striking effects observed on Mpz.…”

Section: Introductionmentioning

confidence: 99%

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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The D355V Mutation Decreases EGR2 Binding To An Element Within The CX32 Promoter

Cited by 8 publications

References 0 publications

Functional Organization of a Schwann Cell Enhancer

Functional Organization of a Schwann Cell Enhancer

Disruption of Krox20-Nab Interaction in the Mouse Leads to Peripheral Neuropathy with Biphasic Evolution

Interactions of Sox10 and Egr2 in myelin gene regulation

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