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UBC Theses and Dissertations

The function of the imprinted transcription factor ASCL2 in mouse trophoblast development Jacob, Karen Jane


The epigenetic phenomenon known as genomic imprinting which leads to the monoallelic expression of genes in a parent-of-origin dependent manner has been linked to the development and function of the placenta in mammals. The imprinted gene, Ascl2, codes for a transcription factor which is expressed from the maternal allele in the placenta and is required for its development. Mice that lack Ascl2 expression from their maternal allele die around mid-gestation of placental failure. The effects of Ascl2 can be studied in vivo, in mice that are Ascl2-deficient and, in vitro in trophoblast stem (TS) cells which provide an excellent model of early placental development. Here we compare the transcriptomes of Ascl2-deficient and wild-type E9.5 placentae and find that a total of 838 coding genes are significantly downregulated in the mutant placentae. These genes were deemed to be potential candidate targets of ASCL2. The downregulation of several genes from this list is verified by qRT-PCR and their location in the placenta investigated by in situ hybridization, verifying their overlap with Ascl2 in the trophoblast. We also investigate the knock-out (KO) placental phenotype of one of these candidate target genes, Hmga2, and recognized a labyrinth phenotype in the Hmga2-KO. We also describe, for the first time, the establishment of Ascl2-deficient TS cells confirming that Ascl2 is dispensable for TS cell establishment and maintenance. We find that Ascl2-deficient TS cells lack expression of several trophoblast cell lineage markers through differentiation suggesting they are unable differentiate into cells of the trophoblast lineage. We also find that Ascl2 candidate gene expression in differentiating Ascl2-deficient TS cells is altered when compared to wild-type. These results provide important insight into the functional role of Ascl2 in the development and differentiation of the cells of the trophoblast lineage.

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