Article

Direct regulation of myelin protein zero expression by the Egr2 transactivator.

Molecular and Cellular Pharmacology Program, School of Veterinary Medicine, University of Wisconsin, 2015 Linden Drive, Madison, WI 53705, USA.
Journal of Biological Chemistry (impact factor: 4.77). 04/2006; 281(9):5453-60. DOI:10.1074/jbc.M512159200
Source: PubMed

ABSTRACT During myelination of the peripheral nervous system, the myelin protein zero (Mpz) gene is induced to produce the most abundant protein component (P(0)) of mature myelin. Although the basal embryonic expression of Mpz in Schwann cells has been attributed to regulation by Sox10, the molecular mechanism for the profound up-regulation of this gene during myelination has not been established. In this study, we have identified a highly conserved element within the first intron of the Mpz gene, which contains binding sites for the early growth response 2 (Egr2/Krox20) transcription factor, a critical regulator of peripheral nerve myelination. Egr2 can transactivate the intron element, and the induction is blocked by two known repressors of Egr2 activity. Using chromatin immunoprecipitation assays, we find that Egr2 binds in vivo to the intron element, but not to the Mpz promoter. Known inducers of Mpz expression such as forskolin and insulin-like growth factor-1 also activate the element in an Egr2-dependent manner. In addition, we found that Egr2 can act synergistically with Sox10 to activate this intron element, suggesting a model in which cooperative interactions between Egr2 and Sox10 mediate a large increase in Mpz expression to the high levels found in myelinating Schwann cells.

0 0
 · 
0 Bookmarks
 · 
27 Views
  • Source
    Article: Genome-wide analysis of EGR2/SOX10 binding in myelinating peripheral nerve.
    Rajini Srinivasan, Guannan Sun, Sunduz Keles, Erin A Jones, Sung-Wook Jang, Courtney Krueger, John J Moran, John Svaren
    [show abstract] [hide abstract]
    ABSTRACT: Myelin is essential for the rapidity of saltatory nerve conduction, and also provides trophic support for axons to prevent axonal degeneration. Two critical determinants of myelination are SOX10 and EGR2/KROX20. SOX10 is required for specification of Schwann cells from neural crest, and is required at every stage of Schwann cell development. Egr2/Krox20 expression is activated by axonal signals in myelinating Schwann cells, and is required for cell cycle arrest and myelin formation. To elucidate the integrated function of these two transcription factors during peripheral nerve myelination, we performed in vivo ChIP-Seq analysis of myelinating peripheral nerve. Integration of these binding data with loss-of-function array data identified a range of genes regulated by these factors. In addition, although SOX10 itself regulates Egr2/Krox20 expression, leading to coordinate activation of several major myelin genes by the two factors, there is a large subset of genes that are activated independent of EGR2. Finally, the results identify a set of SOX10-dependent genes that are expressed in early Schwann cell development, but become subsequently repressed by EGR2/KROX20.
    Nucleic Acids Research 04/2012; 40(14):6449-60. · 8.03 Impact Factor
  • Article: SOX10 regulates expression of the SH3-domain kinase binding protein 1 (Sh3kbp1) locus in Schwann cells via an alternative promoter.
    Chani J Hodonsky, Erica L Kleinbrink, Kira N Charney, Megana Prasad, Seneca L Bessling, Erin A Jones, Rajini Srinivasan, John Svaren, Andrew S McCallion, Anthony Antonellis
    [show abstract] [hide abstract]
    ABSTRACT: The transcription factor SOX10 has essential roles in neural crest-derived cell populations, including myelinating Schwann cells-specialized glial cells responsible for ensheathing axons in the peripheral nervous system. Importantly, SOX10 directly regulates the expression of genes essential for proper myelin function. To date, only a handful of SOX10 target loci have been characterized in Schwann cells. Addressing this lack of knowledge will provide a better understanding of Schwann cell biology and candidate loci for relevant diseases such as demyelinating peripheral neuropathies. We have identified a highly-conserved SOX10 binding site within an alternative promoter at the SH3-domain kinase binding protein 1 (Sh3kbp1) locus. The genomic segment identified at Sh3kbp1 binds to SOX10 and displays strong promoter activity in Schwann cells in vitro and in vivo. Mutation of the SOX10 binding site ablates promoter activity, and ectopic expression of SOX10 in SOX10-negative cells promotes the expression of endogenous Sh3kbp1. Combined, these data reveal Sh3kbp1 as a novel target of SOX10 and raise important questions regarding the function of SH3KBP1 isoforms in Schwann cells.
    Molecular and Cellular Neuroscience 02/2012; 49(2):85-96. · 3.66 Impact Factor
  • Article: Distal enhancers upstream of the Charcot-Marie-Tooth type 1A disease gene PMP22.
    Erin A Jones, Megan H Brewer, Rajini Srinivasan, Courtney Krueger, Guannan Sun, Kira N Charney, Sunduz Keles, Anthony Antonellis, John Svaren
    [show abstract] [hide abstract]
    ABSTRACT: Myelin insulates axons in the peripheral nervous system to allow rapid propagation of action potentials, and proper myelination requires the precise regulation of genes encoding myelin proteins, including PMP22. The correct gene dosage of PMP22 is critical; a duplication of PMP22 is the most common cause of the peripheral neuropathy Charcot-Marie-Tooth Disease (CMT) (classified as type 1A), while a deletion of PMP22 leads to another peripheral neuropathy, hereditary neuropathy with liability to pressure palsies. Recently, duplications upstream of PMP22, but not containing the gene itself, were reported in patients with CMT1A like symptoms, suggesting that this region contains regulators of PMP22. Using chromatin immunoprecipitation analysis of two transcription factors known to upregulate PMP22-EGR2 and SOX10-we found several enhancers in this upstream region that contain open chromatin and direct reporter gene expression in tissue culture and in vivo in zebrafish. These studies provide a novel means to identify critical regulatory elements in genes that are required for myelination, and elucidate the functional significance of non-coding genomic rearrangements.
    Human Molecular Genetics 12/2011; 21(7):1581-91. · 7.64 Impact Factor

Show more

Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

abundant protein component
 
chromatin immunoprecipitation assays
 
conserved element
 
contains binding sites
 
cooperative interactions
 
critical regulator
 
Egr2 activity
 
Egr2-dependent manner
 
growth response 2
 
insulin-like growth factor-1
 
intron element
 
Known inducers
 
large increase
 
molecular mechanism
 
Mpz promoter
 
myelin protein
 
myelinating Schwann cells
 
peripheral nerve myelination
 
peripheral nervous system
 
Schwann cells
 

Scott E LeBlanc