Di Giovannantonio Luca Giovanni, Acampora Dario, Omodei Daniela, Nigro Vincenzo, Barba Pasquale, Barbieri Elisa, Chambers Ian, Simeone Antonio
Institute of Genetics and Biophysics 'Adriano Buzzati-Traverso', CNR, Via P. Castellino, 111, 80131 Naples, Italy.
Institute of Biostructures and Bioimaging, CNR, Via Tommaso De Amicis, 95, 80145 Naples, Italy.
Development. 2021 May 15;148(10). doi: 10.1242/dev.199166. Epub 2021 May 13.
In mammals, the pre-gastrula proximal epiblast gives rise to primordial germ cells (PGCs) or somatic precursors in response to BMP4 and WNT signaling. Entry into the germline requires activation of a naïve-like pluripotency gene regulatory network (GRN). Recent work has shown that suppression of OTX2 expression in the epiblast by BMP4 allows cells to develop a PGC fate in a precise temporal window. However, the mechanisms by which OTX2 suppresses PGC fate are unknown. Here, we show that, in mice, OTX2 prevents epiblast cells from activating the pluripotency GRN by direct repression of Oct4 and Nanog. Loss of this control during PGC differentiation in vitro causes widespread activation of the pluripotency GRN and a deregulated response to LIF, BMP4 and WNT signaling. These abnormalities, in specific cell culture conditions, result in massive germline entry at the expense of somatic mesoderm differentiation. Increased generation of PGCs also occurs in mutant embryos. We propose that the OTX2-mediated repressive control of Oct4 and Nanog is the basis of the mechanism that determines epiblast contribution to germline and somatic lineage.
在哺乳动物中，原肠胚形成前的近端上胚层细胞在BMP4和WNT信号的作用下分化为原始生殖细胞（PGC）或体细胞前体。进入生殖系需要激活一种类似幼稚多能性的基因调控网络（GRN）。最近的研究表明，BMP4抑制上胚层中OTX2的表达，使细胞能够在精确的时间窗口内发育为PGC命运。然而，OTX2抑制PGC命运的机制尚不清楚。在这里，我们表明，在小鼠中，OTX2通过直接抑制Oct4和Nanog来阻止上胚层细胞激活多能性GRN。在体外PGC分化过程中这种控制的缺失会导致多能性GRN的广泛激活以及对LIF、BMP4和WNT信号的失调反应。在特定的细胞培养条件下，这些异常会导致大量细胞进入生殖系，而以体细胞中胚层分化为代价。在突变胚胎中也会出现PGC生成增加的情况。我们认为，OTX2介导的对Oct4和Nanog的抑制性控制是决定上胚层对生殖系和体细胞谱系贡献机制的基础。
