Characterization of Bcor expression in mouse development

Molecular, Cellular, Developmental Biology and Genetics Graduate Program, University of Minnesota, 6-160 Jackson Hall, 321 Church St SE, Minneapolis, MN 55455, USA.
Gene Expression Patterns (Impact Factor: 1.38). 05/2007; 7(5):550-7. DOI: 10.1016/j.modgep.2007.01.006
Source: PubMed


Mutation of the gene encoding the transcriptional corepressor BCOR results in the X-linked disorder Oculofaciocardiodental syndrome (OFCD or MCOPS2). Female OFCD patients suffer from severe ocular, craniofacial, cardiac, and digital developmental defects and males do not survive through gestation. BCOR can mediate transcriptional repression by the oncoprotein BCL6 and has the ability to reduce transcriptional activation by AF9, a known mixed-lineage leukemia (MLL) fusion partner. The essential role of BCOR in development and its ability to modulate activity of known oncogenic proteins prompted us to determine the expression profile of Bcor during mouse development. Identification of independently transcribed exons in the 5' untranslated region of Bcor suggests that three independent promoters control the expression of Bcor in mice. Although Bcor is widely expressed in adult mouse tissues, analysis of known spliced isoforms in the coding region of Bcor reveals differential isoform usage. Whole mount in situ hybridization of mouse embryos shows that Bcor is strongly expressed in the extraembryonic tissue during gastrulation and expression significantly increases throughout the embryo after embryonic turning. During organogenesis and fetal stages Bcor is differentially expressed in multiple tissue lineages, with a notable presence in the developing nervous system. Strikingly, we observed that Bcor expression in the eye, brain, neural tube, and branchial arches correlates with tissues affected in OFCD patients.

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Available from: Joseph A Wamstad
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    • "There appears to be a role for Bcor in the regulation of gene expression in embryonic stem cells, which suggests that Bcor may be important in early tissue differentiation (Wamstad et al., 2008). In mice, the Bcor gene homologue is expressed in neural tube, the branchial arches and in tooth primordial (Wamstad and Bardwell 2007). In a recent study, Fan et al. (2009) investigated mesenchymal stem cells (MSC) from the apical papilla of an OFCD patient who underwent surgical root apex removal on a tooth with radiculomegaly. "
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    ABSTRACT: Oculofaciocardiodental syndrome is a rare genetic disorder affecting ocular, facial, dental, and cardiac systems. The clinical diagnosis of oculofaciocardiodental syndrome can be challenging due to a wide variety of symptoms. Oculofaciocardiodental syndrome is found only in females due to its X-linked inheritance pattern and embryonic lethality for males. Radiculomegaly of canines is the most consistent finding in these patients. In this report we present a female patient with characteristic facial features, as well as a comprehensive overview of oculofaciocardiodental syndrome. Diagnosis of oculofaciocardiodental syndrome in this patient was verified by genetic analysis, during which we found a novel mutation in BCOR.
    Preview · Article · Jul 2011 · The Cleft Palate-Craniofacial Journal
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    • "BCOR was originally identified as a novel BCL6 corepressor (Huynh et al., 2000). It is strongly and specifically expressed during embryonic development (Wamstad and Bardwell, 2007) where it plays a critical role in transcriptional regulation, as BCOR mutations are associated with the X-linked inherited diseases Lenz microphthalmia and Oculofaciocardiodental syndrome (Ng et al., 2004). BCOR copurifies with Polycomb group (PcG) transcriptional repressor proteins and Skp-Cullin-F-box (SCF) ubiquitin E3 ligase components (Gearhart et al., 2006; Sanchez et al., 2007), and the complex can monoubiquinate histone H2A (Gearhart et al., 2006). "
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    ABSTRACT: The transcriptional corepressors BCOR, SMRT, and NCoR are known to bind competitively to the BCL6 BTB domain despite the fact that BCOR has no detectable sequence similarity to the other two corepressors. We have identified a 17 residue motif from BCOR that binds directly to the BCL6 BTB domain and determined the crystal structure of the complex to a resolution of 2.6 A. Remarkably, the BCOR BCL6 binding domain (BCOR(BBD)) peptide binds in the same BCL6 binding site as the SMRT(BBD) peptide despite the lack of any significant sequence similarity between the two peptides. Mutations of critical BCOR(BBD) residues cause the disruption of the BCL6 corepression activities of BCOR, and a BCOR(BBD) peptide blocks BCL6-mediated transcriptional repression and kills lymphoma cells.
    Preview · Article · Mar 2008 · Molecular Cell
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    • "The female lethality observed, arising when the mutant X-linked allele comes from the mother, likely results from paternally-imprinted X-inactivation of the wild type Bcor allele in extra-embryonic tissue of the female offspring (Figure 2D and see discussion). Thus, our results are consistent with a requirement for Bcor in extraembryonic tissue where Bcor is normally highly expressed [22]. The practical consequence of this parent-of-origin effect was that we could not generate extensive numbers of BcorNeo/+ mice and thus phenotypic analysis was limited to the BcorNeo and BcorGt allele-containing chimeras and the remaining six aging female BcorNeo/+ mice that were generated from the two germline-transmitting male chimeras we obtained. "
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    ABSTRACT: Bcor (BCL6 corepressor) is a widely expressed gene that is mutated in patients with X-linked Oculofaciocardiodental (OFCD) syndrome. BCOR regulates gene expression in association with a complex of proteins capable of epigenetic modification of chromatin. These include Polycomb group (PcG) proteins, Skp-Cullin-F-box (SCF) ubiquitin ligase components and a Jumonji C (Jmjc) domain containing histone demethylase. To model OFCD in mice and dissect the role of Bcor in development we have characterized two loss of function Bcor alleles. We find that Bcor loss of function results in a strong parent-of-origin effect, most likely indicating a requirement for Bcor in extraembryonic development. Using Bcor loss of function embryonic stem (ES) cells and in vitro differentiation assays, we demonstrate that Bcor plays a role in the regulation of gene expression very early in the differentiation of ES cells into ectoderm, mesoderm and downstream hematopoietic lineages. Normal expression of affected genes (Oct3/4, Nanog, Fgf5, Bmp4, Brachyury and Flk1) is restored upon re-expression of Bcor. Consistent with these ES cell results, chimeric animals generated with the same loss of function Bcor alleles show a low contribution to B and T cells and erythrocytes and have kinked and shortened tails, consistent with reduced Brachyury expression. Together these results suggest that Bcor plays a role in differentiation of multiple tissue lineages during early embryonic development.
    Full-text · Article · Feb 2008 · PLoS ONE
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