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The basic helix-loop-helix (bHLH) transcription factor ASCL2 plays essential roles in diploid multipotent trophoblast progenitors, intestinal stem cells, follicular T-helper cells, as well as during epidermal development and myogenesis. During early development,  Ascl2  expression is regulated by genomic imprinting and only the maternally inherited allele is transcriptionally active in trophoblast. The paternal allele-specific silencing of  Ascl2  requires expression of the long non-coding RNA  Kcnq1ot1  in  cis  and the deposition of repressive histone marks. Here we show that  Del   7AI  , a 280-kb deletion allele neighboring  Ascl2 , interferes with this process in  cis  and leads to a partial loss of silencing at  Ascl2 . Genetic rescue experiments show that the low level of  Ascl2  expression from the paternal  Del   7AI   allele can rescue the embryonic lethality associated with maternally inherited  Ascl2  mutations, in a level-dependent manner. Despite their ability to support development to term, the rescued placentae have a pronounced phenotype characterized by severe hypoplasia of the junctional zone, expansion of the parietal trophoblast giant cell layer, and complete absence of invasive glycogen trophoblast cells. Transcriptome analysis of ectoplacental cones at E7.5 and differentiation assays of  Ascl2  mutant trophoblast stem cells show that ASCL2 is required for the emergence or early maintenance of glycogen trophoblast cells during development. Our work identifies a new  cis -acting mutation interfering with  Kcnq1ot1  silencing function and establishes a novel critical developmental role for the transcription factor ASCL2.

Transcription factor ASCL2 is required for development of the glycogen trophoblast cell lineage