The HAND1 basic helix-loop-helix transcription factor regulates trophoblast differentiation via multiple mechanisms.
The basic helix-loop-helix (bHLH) transcription factor genes Hand1 and Mash2 are essential for placental development in mice. Hand1 promotes differentiation of trophoblast giant cells, whereas Mash2 is required for the maintenance of giant cell precursors, and its overexpression prevents giant cell differentiation. We found that Hand1 expression and Mash2 expression overlap in the ectoplacental cone and spongiotrophoblast, layers of the placenta that contain the giant cell precursors, indicating that the antagonistic activities of Hand1 and Mash2 must be coordinated. MASH2 and HAND1 both heterodimerize with E factors, bHLH proteins that are the DNA-binding partners for most class B bHLH factors and which are also expressed in the ectoplacental cone and spongiotrophoblast. In vitro, HAND1 could antagonize MASH2 function by competing for E-factor binding. However, the Hand1 mutant phenotype cannot be solely explained by ectopic activity of MASH2, as the Hand1 mutant phenotype was not altered by further mutation of Mash2. Interestingly, expression of E-factor genes (ITF2 and ALF1) was down-regulated in the trophoblast lineage prior to giant cell differentiation. Therefore, suppression of MASH2 function, required to allow giant cell differentiation, may occur in vivo by loss of its E-factor partner due to loss of its expression and/or competition from HAND1. In giant cells, where E-factor expression was not detected, HAND1 presumably associates with a different bHLH partner. This may account for the distinct functions of HAND1 in giant cells and their precursors. We conclude that development of the trophoblast lineage is regulated by the interacting functions of HAND1, MASH2, and their cofactors.
Scott
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Program in Development and Fetal Health, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario Canada.
Anson-Cartwright
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Riley
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Reda
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Cross
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D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D001667:Binding, Competitive; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D005260:Female; D005786:Gene Expression Regulation; D015726:Giant Cells / Q000166:cytology / Q000378:metabolism; D018257:Helix-Loop-Helix Motifs; D051379:Mice; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins; D009928:Organ Specificity; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D051381:Rats; D020218:Response Elements / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D051820:TCF Transcription Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D000073940:Transcription Factor 4; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014327:Trophoblasts / Q000166:cytology* / Q000378:metabolism
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D051820:TCF Transcription Factors; D015534:Trans-Activators; D000073940:Transcription Factor 4; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors; C489311:Ascl2 protein, mouse; C489312:Ascl2 protein, rat; C095572:Hand1 protein, mouse; C544912:TCF7L1 protein, human; C489532:Tcf12 protein, mouse; C090743:Tcf4 protein, mouse; C491192:Tcf4 protein, rat; C544913:Tcf7l1 protein, mouse; C553060:Tcf7l1 protein, rat; C097341:helix-loop-helix protein, eHAND; C073366:TCF12 protein, human