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A regulatory loop involving Dies1 and miR‐125a controls BMP4 signaling in mouse embryonic stem cells
Author(s) -
Parisi Silvia,
Battista Marica,
Musto Anna,
Navarra Angelica,
Tarantino Carolina,
Russo Tommaso
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.12-211607
Subject(s) - embryonic stem cell , microbiology and biotechnology , bone morphogenetic protein 4 , epiblast , biology , stem cell , nodal signaling , signal transduction , cellular differentiation , gene , genetics , gastrulation
Bone morphogenetic protein 4 (BMP4) plays an important role in maintaining embryonic stem cells (ESCs) in the undifferentiated state and in the regulation of lineage commitment. We recently identified a transmembrane protein, named Dies1, the suppression of which by RNA interference blocks mouse ESC differentiation by interfering with the BMP4 signaling. We asked whether modulation of Dies1 levels could be a physiological mechanism to regulate ESC pluripotency and/or differentiation. We demonstrated that miR‐125a targets Dies1 and regulates its expression in ESCs. The overexpression of miR‐125a impairs differentiation, and this effect is specifically mediated by Dies1 down‐regulation and accompanied by a decrease of BMP4 signaling. We also found that Dies1 is associated with BMP4 receptor complex and that BMP4 activates the transcription of miR‐125a gene. Therefore, a feedback loop exists that sets ESC sensitivity to BMP4. The analysis of this regulatory mechanism revealed that miR‐125a overexpression and the consequent inhibition of the BMP4 signaling arrest the cells in the epiblast stem cell (epiSC) status, due to the concomitant activation of the Nodal/Activin pathway.—Parisi, S., Battista, M., Musto, A., Navarra, A., Tarantino, C., Russo, T. A regulatory loop involving Dies1 and miR‐125a controls BMP4 signaling in mouse embryonic stem cells. FASEB J. 26, 3957–3968 (2012). www.fasebj.org