A genome wide RNAi screen in mouse embryonic stem cells identifies Mp1 as a key mediator of differentiation

Despite intense investigation of intrinsic and extrinsic factors that regulate pluripotency, the process of initial fate commitment of embryonic stem (ES) cells is still poorly understood. Here, we used a genome wide shRNA screen in mouse ES cells to identify genes that are essential for initiation of differentiation. Knockdown of the scaffolding protein Mek binding protein 1 (Mp1, also known as Lamtor3, Map2k1ip1) stimulated self-renewal of ES cells, blocked differentiation and promoted proliferation. Fibroblast growth factor 4 (FGF4) signaling is required for initial fate commitment of ES cells. Knockdown of Mp1 inhibited FGF4-induced differentiation but did not alter FGF4 driven proliferation. This uncoupling of differentiation and proliferation was also observed when oncogenic Ras isoforms were over expressed in ES cells. Knockdown of Mp1 redirected FGF4 signaling from differentiation towards pluripotency and upregulated the pluripotency-related genes Esrrb, Rex1, Tcl1 and Sox2.

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Westerman BA, Braat AK, Taub N, Potman M, Vissers JH, Blom M, Verhoeven E, Stoop H, Gillis A, Velds A, Nijkamp W, Beijersbergen R, Huber LA, Looijenga LH, van Lohuizen M