Primordial Germ Cell Development in the Mouse
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 germline, and that erasure coincides with gonad colonization. We are interested in understanding the mechanisms which regulate these diverse programs in early gonadal germ cells.
Mouse Models of Imprinting in the Prader-Willi / Angleman Syndrome Region
Recently we have united with Cami Brannan’s lab using mouse genetics to investigate mechanisms underlying genetic imprinting in the Prader-Willi / Angelman Syndrome region. Most genes are equally expressed from both the maternal and paternal alleles. However, some genes are imprinted, and are expressed from only one parental allele. Prader-Willi and Angelman Syndromes are clinically distinct, but result 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. In the case of Prader-Willi, deletions encompassing the 5’ end of the SNRPN gene prevent not only SNRPN expression, but also several other paternal only expressed genes over approximately 1.5 megabases. To test the idea that an Imprinting Center, located upstream of SNRPN, is responsible for imprinted expression in the region, the Brannan lab created a 35 kilobase deletion in the 5’ region of the mouse Snrpn gene. When this deletion is transmitted from a male, the pups lack expression of numerous genes in the PWS region, demonstrating that the IC does regulate several nearby genes. Furthermore, the pups exhibit some traits characteristic of PWS infants. Current investigations are in two general directions: 1) to investigate the mechanisms by which the imprinting center regulates gene expression in this region, and 2) to explore the contributions of individual genes in the PWS region to the complex Prader-Willi phenotype.
citations