Stem Cell and Regenerative Medicine Center, Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA.
Department of Neuroscience and Physiology, Neuroscience Institute, NYU Langone Medical Center, New York, NY 10016, USA.
Stem Cell Reports. 2020 Nov 10;15(5):1047-1055. doi: 10.1016/j.stemcr.2020.10.003. Epub 2020 Oct 29.
Enhancing repair of myelin is an important therapeutic goal in many neurological disorders characterized by demyelination. In the healthy adult brain, ventral neural stem cells (vNSCs) in the subventricular zone, marked by GLI1 expression, do not generate oligodendrocytes. However, in response to demyelination, their progeny are recruited to lesions where they differentiate into oligodendrocytes and ablation of GLI1 further enhances remyelination. GLI1 and GLI2 are closely related transcriptional activators but the role of GLI2 in remyelination by vNSCs is not clear. Here, we show that genetic ablation of Gli1 in vNSCs increases GLI2 expression and combined loss of both transcription factors decreases the recruitment and differentiation of their progeny in demyelinated lesions. These results indicate that GLI1 and GLI2 have distinct, non-redundant functions in vNSCs and their relative levels play an essential role in the response to demyelination.
增强髓鞘修复是许多脱髓鞘神经疾病的重要治疗目标。在健康的成年大脑中，室管膜下区的腹侧神经干细胞（vNSCs）表达 GLI1，不产生少突胶质细胞。然而，在脱髓鞘反应中，它们的后代被招募到病变部位，分化为少突胶质细胞，而 GLI1 的消融进一步增强了髓鞘再生。GLI1 和 GLI2 是密切相关的转录激活因子，但 GLI2 在 vNSCs 中的髓鞘再生作用尚不清楚。在这里，我们表明 vNSCs 中 Gli1 的遗传缺失会增加 GLI2 的表达，而两种转录因子的联合缺失会减少其后代在脱髓鞘病变中的募集和分化。这些结果表明，GLI1 和 GLI2 在 vNSCs 中具有不同的、非冗余的功能，它们的相对水平在对脱髓鞘的反应中起着至关重要的作用。
