Mastrototaro Giuseppina, Zaghi Mattia, Massimino Luca, Moneta Matteo, Mohammadi Neda, Banfi Federica, Bellini Edoardo, Indrigo Marzia, Fagnocchi Giulia, Bagliani Anna, Taverna Stefano, Rohm Maria, Herzig Stephan, Sessa Alessandro
Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Neurimmunology Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Front Cell Dev Biol. 2021 Feb 23;9:641410. doi: 10.3389/fcell.2021.641410. eCollection 2021.
gene is associated with multiple developmental disorders presenting several neurological aspects. The relative protein is involved in the modulation of important cellular pathways and master regulators of transcriptional output, including nuclear receptor repressors, Wnt signaling, and MECP2 protein. However, TBL1XR1 mutations (including complete loss of its functions) have not been experimentally studied in a neurological context, leaving a knowledge gap in the mechanisms at the basis of the diseases. Here, we show that knock-out mice exhibit behavioral and neuronal abnormalities. Either the absence of TBL1XR1 or its point mutations interfering with stability/regulation of NCOR complex induced decreased proliferation and increased differentiation in neural progenitors. We suggest that this developmental unbalance is due to a failure in the regulation of the MAPK cascade. Taken together, our results broaden the molecular and functional aftermath of TBL1XR1 deficiency associated with human disorders.
基因与多种呈现出若干神经学方面特征的发育障碍相关联。相关蛋白质参与重要细胞通路的调节以及转录输出的主要调节因子，包括核受体阻遏物、Wnt信号传导和MECP2蛋白。然而，TBL1XR1突变（包括其功能的完全丧失）尚未在神经学背景下进行实验研究，这在这些疾病的发病机制方面留下了知识空白。在此，我们表明基因敲除小鼠表现出行为和神经元异常。TBL1XR1的缺失或其干扰NCOR复合体稳定性/调节的点突变均导致神经祖细胞增殖减少和分化增加。我们认为这种发育失衡是由于MAPK级联调节失败所致。综上所述，我们的结果拓宽了与人类疾病相关的TBL1XR1缺陷的分子和功能后果。
