Disease relevance of Ascl2

• Disruption of the Mash2 gene leads to early intrauterine death caused by placental insufficiency with an absent spongiotrophoblast and an underdeveloped chorion [1].
• These observations demonstrate a crucial role for HIF in the formation of the spongiotrophoblast that is probably regulated by Mash2, and suggest a complex interaction between hypoxia, HIF and Mash2 in the formation of the spongiotrophoblast [2].

High impact information on Ascl2

• This murine gene maps to the distal region of chromosome 7, within a cluster of imprinted genes, including insulin-2, insulin-like growth factor-2, H19 and Mash2 (refs 14-18) [3].
• Genomic imprinting of Mash2, a mouse gene required for trophoblast development [4].
• First, Mash2+/- embryos inheriting a wild-type allele from their father die at the same stage as -/- embryos, with a similar placental phenotype [4].
• Finally, we have genetically and physically mapped Mash2 to the distal region of chromosome 7, within a cluster of imprinted genes, including insulin-2, insulin-like growth factor-2 and H19 [4].
• Mash-2 transcripts are not found in primary and secondary giant cells, yolk sac or allantois at any post-implantation stage, and are present only transiently and at low levels in the embryo during gastrulation [5].

Biological context of Ascl2

• In contrast Mash-2, which is expressed in spongiotrophoblast cells of the placenta, was unaffected by the enhancer deletion [6].
• Surprisingly, the three maternally expressed genes are regulated very differently by DNA methylation; p57(Kip2) is activated, Kvlqt1 is silenced, and Mash2 is unaffected in mice lacking DNA methyltransferase [7].
• We can therefore conclude that the primary and cell-autonomous function of Mash2 appears to be an involvement in the development of diploid trophoblast cells in the ectoplacental cone to form the spongiotrophoblast cell layer of the mature chorioallantoic placenta [8].
• Targeted mutagenesis of Mash2 revealed that loss of function results in embryonic lethality at midgestation, due to placental failure associated with a lack of spongiotrophoblast and reduced labyrinthine trophoblast layers [8].
• For the further study of Mash2 function in development of the trophoblast cell lineage, we have performed chimeric analysis combining Mash2 mutant and wild-type embryos [8].

Anatomical context of Ascl2

• The mouse gene Mash2 encodes a transcription factor required for development of trophoblast progenitors [4].
• Mash-2 transcripts are found in the female germ line and in the embryo throughout preimplantation development, but are highly expressed later only in the ectoplacental cone, the chorion and their derivatives in the placenta [5].
• Mash-2 expression begins during preimplantation development, but is restricted to trophoblasts after the blastocyst stage [9].
• In order to study the Mash2 imprinting mechanism, we have created a new allele at this locus carrying a targeted insertion of an IRES (internal ribosome entry site)-lacZ cassette within the 3' untranslated region of the gene (referred to as "Mash2-lacZ") [10].
• Experiments using placental stem cells (TS cells) derived from Hif1alpha-/- Hif2alpha-/- (Hifalpha-/-) and Arnt-/- mice indicate that there is increased expression of the labyrinthine specific transcription factors GCM and TFEB and a deficiency in the spongiotrophoblast transcription factor Mash2 [2].

Physical interactions of Ascl2

• I-mfa interacted with the bHLH protein Mash2, a negative regulator of trophoblast giant cell formation, and inhibited its transcriptional activity in cell culture [11].

Regulatory relationships of Ascl2

• Mash2 is expressed in oogenesis and preimplantation development but is not required for blastocyst formation [12].

Other interactions of Ascl2

• We have isolated two mouse homologues of Achaete-Scute Complex genes, Mash-1 and Mash-2, by using the conservation of the basic-helix-loop-helix domain in this family [13].
• Cx31 knockout TS cells revealed an accelerated differentiation process to giant cells compared to controls, indicated by an overall shift in expression of connexins and marker genes such as Mash2, Pl-1, and Tpbpa [14].
• Developmental restriction of Mash-2 expression in trophoblast correlates with potential activation of the notch-2 pathway [9].
• Furthermore, we have addressed the question of a requirement for DNA methylation for the Mash2 imprinting mechanism by crossing our Mash2-lacZ mice with mice mutant for Dnmt1 (DNA-methyltransferase1) [10].
• Genomic imprinting of Mash2 has been previously reported; transcriptional inactivation of the paternal wild-type allele in heterozygotes carrying a maternal null allele results in a null-equivalent embryonic lethal phenotype [10].

Analytical, diagnostic and therapeutic context of Ascl2

• To analyse the role of Mash-2 in development, we have used gene targeting to generate mice having no Mash-2 function [5].

References