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

Desmazières, Anne; Decker, Leslie M.; Vallat, Jean‐Michel; Charnay, Patrick; Gilardi-Hebenstreit, Pascale

doi:10.1523/jneurosci.5187-07.2008

Cited by 30 publications

(35 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several independent studies have shown Egr2 in conjunction with Nab expression is critical for peripheral myelination (Le et al, 2005b; Desmazieres et al, 2008; Baloh et al, 2009). Thus, knockout mice with hypomyelination phenotype (e.g.…”

Section: Resultsmentioning

confidence: 99%

“…Although the association of Chd4 with NAB coregulators provided the mechanistic basis for this study, the resulting phenotype is significantly less severe than that caused by deletion of both NAB genes, or by knock-in of a NAB-resistant allele of Egr2 (Le et al, 2005b; Desmazieres et al, 2008; Baloh et al, 2009). One possible explanation could be redundancy with Chd3.…”

Section: Discussionmentioning

confidence: 97%

“…Egr2 target genes include several lipid biosynthetic genes and major myelin components, including myelin protein zero (Mpz) and peripheral myelin protein 22 (Pmp22) (Nagarajan et al, 2001). The activity of Egr2 requires interaction with the NGFI-A/Egr binding protein (Nab1 and Nab2) transcriptional co-regulators (Le et al, 2005b; Desmazieres et al, 2008; Baloh et al, 2009), which directly bind and repress Egr2 transcriptional activity (Russo et al, 1995; Svaren et al, 1996). …”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The Nucleosome Remodeling and Deacetylase Chromatin Remodeling (NuRD) Complex Is Required for Peripheral Nerve Myelination

Hung¹,

Kohnken²,

Svaren³

2012

J. Neurosci.

View full text Add to dashboard Cite

Several key transcription factors and coregulators important to peripheral nerve myelination have been identified, but the contributions of specific chromatin remodeling complexes to peripheral nerve myelination have not been analyzed. Chromodomain helicase DNA-binding protein 4 (Chd4) is the core catalytic subunit of the Nucleosome Remodeling and Deacetylase (NuRD) chromatin remodeling complex. Previous studies have shown Chd4 interacts with Nab (NGFI-A/Egr-binding) corepressors, which are required for Early growth response 2 (Egr2/Krox20), to direct peripheral nerve myelination by Schwann cells. In this study, we examined the developmental importance of the NuRD complex in peripheral nerve myelination through the generation of conditional Chd4 knockout mice in Schwann cells (Chd4loxP/loxP; P0-cre). Chd4 conditional null mice were found to have delayed myelination, radial sorting defects, hypomyelination, and the persistence of promyelinating Schwann cells. Loss of Chd4 leads to elevated expression of immature Schwann cell genes (Id2, c-Jun, and p75), and sustained expression of the promyelinating Schwann cell gene, Oct6/Scip, without affecting the levels of Egr2/Krox20. Furthermore, Schwann cell proliferation is upregulated in Chd4 null sciatic nerve. In vivo ChIP studies reveal recruitment of Chd4 and another NuRD component, Mta2, to genes that are positively and negatively regulated by Egr2 during myelination. Taken together, these results underscore the necessity of Chd4 function to guide proper terminal differentiation of Schwann cells and implicate the NuRD chromatin remodeling complex as a requisite factor in timely and stable peripheral nerve myelination.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Nucleosome Remodeling and Deacetylase Chromatin Remodeling (NuRD) Complex Is Required for Peripheral Nerve Myelination

Hung¹,

Kohnken²,

Svaren³

2012

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Interestingly, Egr1 has previously been shown to bind to cognate sites within the human Socs1 promoter and to positively regulate Socs1 expression in macrophages [37]. As one of the binding sites is conserved in the murine promoter, it is possible that Egr2 is able to bind to the Socs1 promoter directly and repress its activity, perhaps in combination with a member of the cofactor family of Nab proteins (for example, see [38]). However, it is likely that regulation is complex, potentially depending on interplay with other transcription factors such as the established Egr2 repressor Gfi-1B [39], as the effects of Egr2 manipulation on Socs1 expression, as shown in Fig.…”

Section: Discussionmentioning

confidence: 99%

Early growth response 2 regulates the survival of thymocytes during positive selection

2009

View full text Add to dashboard Cite

The early growth response (Egr) transcription factor family regulates multiple steps during T-cell development. We examine here the role played by Egr2 in positive selection. In double-positive cells, Egr2 is upregulated immediately following TCR ligation, and its expression requires both the MAPK and calcineurin signaling pathways. Inducible transgenic and knockout mice were generated to cause gain-or loss-of-function of Egr2 in double-positive cells, and had reciprocal effects; more mature single-positive cells were made when Egr2 was overexpressed, and fewer when Egr2 was absent. These defects were associated with changes in the survival of positively selected cells rather than perturbation of positive selection or immediate post-selection signaling. The survival function of Egr2 at least partly depends upon its ability to activate the cytokine-mediated survival pathway, likely through negative regulation of both the IL-7R and suppressor of cytokine signaling 1 (Socs1), the molecular switch whose downregulation normally results in restored responsiveness to cytokine signaling following selection. While gain of Egr2 caused a decrease in Socs1 mRNA, loss of Egr2 resulted in downregulation of IL-7R, upregulation of Socs1, and inhibition of Stat5 phosphorylation and IL-7-mediated survival post-selection. Therefore, expression of Egr2 following positive selection links the initial TCR signaling event to subsequent survival of signaled cells. , and Egr3 is also required for the post-b-selection proliferative burst to occur [12]. These transcription factors are also induced rapidly following ligation of the abTCR, both during thymocyte selection [15] and in mature T cells responding to antigen-MHC, where Egr1 has a role in upregulation of IL2 transcription [16], and Egr2 and Egr3 are required for induction of anergy [17,18], and regulate expression of FasL [19,20]. Through its control of self-tolerance, Egr2 has also been implicated in the development of late-onset autoimmune disease [21] and is required for the development and maturation of NKT cells [22].Upregulation of Egr proteins during positive selection is dependent upon the Ras/MAPK pathway [13]. Egr proteins are direct transcriptional targets of ternary complex factor Sap-1, which is itself a substrate of Erk and essential for positive selection [23]. In addition, Egr2 and Egr3 are regulated by calcineurin signaling, likely via NFAT [13,20,22]. Both Egr1 and Egr3 have roles in positive selection. Egr1 overexpression enhances positive selection of cells with low affinity TCR [24]. Conversely, Egr1-deficient mice have impaired positive selection [25]; although the initial TCR signal is transduced, cells stall at the DP to SP transition, resulting in a numerical decrease in CD4 and CD8 SP. Animals doubly deficient for both Egr1 and Egr3 have a similar but more marked selection phenotype, and CD8 differentiation is significantly impaired [14]. For both Egr1 and Egr3, the principal reason for the alterations in SP cell number is a change in the cells' susceptibi...

show abstract

“…Alkaline phosphatase activity was revealed using the NBT/ or INT/BCIP substrates (Roche). Mouse immunolabelling was performed using rabbit anti-Krox20 (Desmazières et al, 2008) and rat anti-GFP (Nacalai Tesque) antibodies. For double labelling, in situ hybridization was performed as above and rat anti-HA antibody (Roche) was added with the anti-DIG antibody.…”

Section: In Situ Hybridization Immunolabelling and X-gal Stainingmentioning

confidence: 99%

Rostral hindbrain patterning involves the direct activation of aKrox20transcriptional enhancer by Hox/Pbx and Meis factors

et al. 2008

View full text Add to dashboard Cite

The morphogenesis of the vertebrate hindbrain involves the generation of metameric units called rhombomeres (r), and Krox20 encodes a transcription factor that is expressed in r3 and r5 and plays a major role in this segmentation process. Our knowledge of the basis of Krox20 regulation in r3 is rather confusing, especially concerning the involvement of Hox factors. To investigate this issue, we studied one of the Krox20 hindbrain cis-regulatory sequences, element C, which is active in r3-r5 and which is the only initiator element in r3. We show that element C contains multiple binding sites for Meis and Hox/Pbx factors and that these proteins synergize to activate the enhancer. Mutation of these binding sites allowed us to establish that Krox20 is under the direct transcriptional control of both Meis (presumably Meis2) and Hox/Pbx factors in r3. Furthermore, our data indicate that element C functions according to multiple modes, in Meis-independent or -dependent manners and with different Hox proteins, in r3 and r5. Finally, we show that the Hoxb1 and Krox20 expression domains transiently overlap in prospective r3, and that Hoxb1 binds to element C in vivo, supporting a cell-autonomous involvement of Hox paralogous group 1 proteins in Krox20 regulation. Altogether, our data clarify the molecular mechanisms of an essential step in hindbrain patterning. We propose a model for the complex regulation of Krox20, involving a novel mode of initiation, positive and negative controls by Hox proteins, and multiple direct and indirect autoregulatory loops.

show abstract

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

Cited by 30 publications

References 54 publications

The Nucleosome Remodeling and Deacetylase Chromatin Remodeling (NuRD) Complex Is Required for Peripheral Nerve Myelination

The Nucleosome Remodeling and Deacetylase Chromatin Remodeling (NuRD) Complex Is Required for Peripheral Nerve Myelination

Early growth response 2 regulates the survival of thymocytes during positive selection

Rostral hindbrain patterning involves the direct activation of aKrox20transcriptional enhancer by Hox/Pbx and Meis factors

Contact Info

Product

Resources

About