Abstract
Imprinted genes are expressed primarily from one parental allele by virtue of a germ line epigenetic process. Achaete-scute complex homolog 2 (Ascl2 aka Mash2) is a maternally expressed imprinted gene that plays a key role in placental and intestinal development. Loss-of-function of Ascl2 results in an expansion of the parietal trophoblast giant cell (P-TGC) lineage, an almost complete loss of Trophoblast specific protein alpha (Tpbpa) positive cells in the ectoplacental cone and embryonic failure by E10.5. Tpbpa expression marks the progenitors of some P-TGCs, two additional trophoblast giant cell lineages (spiral artery and canal), the spongiotrophoblast and the glycogen cell lineage. Using a transgenic model, here we show that elevated expression of Ascl2 reduced the number of P-TGC cells by 40%. Elevated Ascl2 also resulted in a marked loss of the spongiotrophoblast and a substantial mislocalisation of glycogen cells into the labyrinth. In addition, Ascl2-Tg placenta contained considerably more placental glycogen than wild type. Glycogen cells are normally located within the junctional zone in close contact with spongiotrophoblast cells, before migrating through the P-TGC layer into the maternal decidua late in gestation where their stores of glycogen are released. The failure of glycogen cells to release their stores of glycogen may explain both the inappropriate accumulation of glycogen and fetal growth restriction observed late in gestation in this model. In addition, using in a genetic cross we provide evidence that Ascl2 requires the activity of a second maternally expressed imprinted gene, Pleckstrin homology-like domain, family a, member 2 (Phlda2) to limit the expansion of the spongiotrophoblast. This “belts and braces” approach demonstrates the importance of genomic imprinting in regulating the size of the placental endocrine compartment for optimal placental development and fetal growth.
Highlights
Genomic imprinting is a remarkable process whereby certain genes are preferentially silenced on one parental allele as a consequence of epigenetic events initiated in the germ line (Surani, 1998)
Adenovirus driven overexpression of Ascl2 at 10-fold the normal level was found to down-regulate expression of both Trophoblast specific protein alpha (Tpbpa) and Prl3d1 in trophoblast stem cells cultured under stem cell conditions, alongside reduced expression of Phlda2 (Takao et al, 2012) (Supplemental Table 1)
Previous studies in mice examining the consequences of reduced expression of Ascl2 have suggested a pivotal role for this gene in repressing the expansion of the parietal trophoblast giant cell lineage (Guillemot et al, 1995, 1994; Tanaka et al, 1997; OhMcGinnis et al, 2011)
Summary
Genomic imprinting is a remarkable process whereby certain genes are preferentially silenced on one parental allele as a consequence of epigenetic events initiated in the germ line (Surani, 1998). Achaete-scute complex homolog 2 (Ascl aka Mash2) was one of the first imprinted genes to be knocked out in mice (Guillemot et al, 1995). These studies demonstrated that fetal survival beyond E10.5 requires the maternal Ascl allele (Guillemot et al, 1995, 1994). Loss of function restricted to the embryo had no overt consequence during gestation highlighting a requirement for placental Ascl in the transition to the mature chorioallantoic placenta (Tanaka et al, 1997). The mature mouse placenta is organised into the histologically distinct labyrinth zone, junctional zone and maternal decidua, all of which are interspersed with trophoblast giant cells (TGCs) (John and Hemberger, 2012; Rai and Cross, 2014).
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