International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


Menheniott T R
University of Bath, Centre for Regenerative Medicine, Department of Biology and Biochemistry

Co-Authors: 1) CharalambousM, 2) Bennett W R, 1) KellyS M, 3) DellG, 1) Ward A
Institutions: 1) University of Bath, Centre for Regenerative Medicine, Department of Biology and Biochemistry. 2) University of Manchester, UK Centre for Tissue Engineering. 3) University of Bristol, Department of Biochemistry

The Igf2 gene is imprinted at most sites of its expression, but escapes imprinting in the choroid plexus and leptomeninges of the brain. Imprinting of Igf2 has been shown to be dependent upon a differentially methylated imprinting control region (ICR) that lies in the 5' flank of the neighbouring H19 gene and acts as an insulator to block enhancers that are situated further downstream. We have found that enhancers for brain-specific expression of Igf2 reside within a 2kb region located centrally between Igf2 and H19. These elements permit bi-allelic expression of Igf2 because of their location upstream of the ICR, avoiding its influence on the maternal as well as the paternal chromosomes. Consistent with this proposal we have shown that the ICR maintains differential allelic methylation in the choroid plexus. To further address potential roles played by epigenetic factors, we have developed in vitro culture systems for choroid plexus epithelial tissue. In addition, it appears that bi-allelic Igf2 expression in the choroid plexus is limited to a subpopulation of epithelial cells. We are investigating genes in the Notch/Delta signalling pathway as candidate regulators that establish such variegation in cell fate. In summary, a combination of enhancer location, epigenetic mechanisms and variegated transcriptional controls appear to regulate Igf2 expression in the choroid plexus. By elucidating the molecular cues that reprogram Igf2 from a mono to bi-allelic mode of expression in the brain, we hope to gain an insight to the loss of Igf2 imprinting that occurs in some overgrowth disorders.

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