Mutations in the transcriptional corepressor BCOR results in X-linked MCOPS2 (microphthalmia syndromic 2) disorders, including Oculofaciocardiodental syndrome (OFCD) and MAA2-associated Lenz microphthalmia. BCOR regulates gene expression in association with a Polycomb group like complex of proteins capable of epigenetic modification of chromatin, including the H2A E3 ubiquitin ligases RING1A/B and the histone demethylase FBXL10. To evaluate the role of Bcor in mouse development, we determined the expression pattern of Bcor during embryogenesis and generated multiple mutant alleles of Bcor in mice and ES cells. Bcor is strongly expressed in extraembryonic tissue during mid-gestation and in embryonic structures that correlate with tissues affected in OFCD patients. Bcor loss-of-function in mice results in a strong parent-of-origin effect, most likely indicating a requirement for Bcor in extraembryonic development. In vitro differentiation of embryonic stem (ES) cells harboring Bcor loss-of-function alleles demonstrates a role for Bcor in the regulation of gene expression very early in the differentiation of ES cells into ectoderm, mesoderm and downstream hematopoietic lineages. Chimeric mice generated with these same Bcor loss-of-function ES cells, display reduced contribution to hematopoietic lineages, ocular abnormalities and tail malformations. To circumvent the early embryonic requirement of Bcor in development, we created a conditional allele of Bcor in ES cells and mice that mimics a mutation found in OFCD patients. Ubiquitous inactivation of Bcor in mice results in male lethality prior to embryonic turning and female lethality late in gestation. Additionally, ablation of Bcor in ES cells results in the up regulation of important developmental regulators. In total, these results indicate that Bcor plays an essential role in the differentiation of multiple tissue lineages during early embryonic and extraembryonic development.
University of Ph.D. dissertation. June 2009. Major: Molecular, Cellular, Developmental Biology and Genetics. Advisor: Vivian J. Bardwell, Ph.D., 1 computer file (PDF); iii, 174 pages.
Wamstad, Joseph Alan.
The role of the transcriptional corepressor Bcor in embryonic stem cells and mouse development..
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