Mouse Models of Imprinting in the Prader-Willi / Angleman Syndrome Region
Most genes are equally expressed from both the maternal and paternal alleles. However, some genes are subject to imprinting, a process that results in expression of only one allele. Prader-Willi and Angelman Syndromes are clinically distinct syndromes affecting the same genes, and from opposite patterns of imprinting of human chromosome 15q11-q13. Angelman Syndrome results from defects in the maternal copy of the UBE3A gene, while Prader-Willi Syndrome results from defects in the paternal copy of several contiguous genes from this chromosomal region. While most patients have large 4 megabase deletions that remove the entire locus, rare Prader-Willi patients have much smaller microdeletions that regulate genes in located over 3-4 megabase. In the case of Prader-Willi, deletions removing a small element known as the PWS-IC prevent expression of several genes normally transcribed only from the paternal chromosome. We have created mutations in the analogous element in the mouse genone to understand how this element functions. We are using these models to investigate the contribution of individual genes to the complex PWS phenotype. Similarly some Angeleman syndrome patients have deletions of an element known as the AS-IC. The AS-IC is necessary not only to silence paternal-only genes on the maternally inherited chromosome, but also for maternal expression of UBE3A. Investigations into AS-IC function have been hampered by the inability to identify a similar element in the mouse. Current efforts focus on characterizing the murine AS-IC.
Epigenetic Reprogramming in the Fetal Germ Line
As the embryonic progenitors of mature gametes, primordial germ cells (PGCs) play critical roles in both reproduction and embryogenesis. During development, germ cells first appear in the extraembryonic tissues and subsequently migrate to the developing fetal gonad. Shortly after arrival in the gonad, the PGCs end a period of rapid division and differentiate along sex specific pathways. XY germ cells enter a mitotic arrest, while XX germ cells enter meiotic prophase. Recent evidence suggests that primordial germ cells are also responsible for the erasure of epigenetic marks in the germ line, and that erasure coincides with gonad colonization. We are interested in understanding the mechanisms that regulate these diverse programs in early germ cells.
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