Abstract
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 Del7AI, 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 Del7AI 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.
Highlights
The Ascl2 gene—previously known as Mash2—was originally cloned as a mammalian homologue of Drosophila achaete-scute genes and codes for a group A basic helix-loop-helix (bHLH) transcription factor [1,2]
These studies have shown that ASCL2-E-protein complexes promote transcriptional activation, during myogenesis ASCL2 inhibits the action of bHLH myogenic factors by sequestration of E proteins [6], suggesting context-dependent mechanisms for ASCL2 function
Expression studies suggested that total Ascl2 levels might be increased in +/Del7AI placentae at E9.5 compared to their wild-type littermates [24]
Summary
The Ascl gene—previously known as Mash2—was originally cloned as a mammalian homologue of Drosophila achaete-scute genes and codes for a group A bHLH transcription factor [1,2]. Ascl was shown to play critical roles in a number of other cell types and developmental processes, including intestinal stem cells [4], epidermal development [5], myogenesis [6], and follicular T-helper cells [7]. ASCL2 acts by hetero-dimerization with ubiquitous bHLH factors of the E protein family, such as TCF3/ E12-E47, TCF4/E2-2/ITF2, and TCF12/HEB/ALF1 [4,6,8]. These studies have shown that ASCL2-E-protein complexes promote transcriptional activation, during myogenesis ASCL2 inhibits the action of bHLH myogenic factors by sequestration of E proteins [6], suggesting context-dependent mechanisms for ASCL2 function
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
