University of Manchester, Faculty of Biology, Medicine and Health, School of Biological Sciences, Michael Smith Building, Oxford Rd. Manchester M13 9PY, UK.
Biomolecules. 2020 Mar 23;10(3):485. doi: 10.3390/biom10030485.
Notch3 is one of four mammalian Notch proteins, which act as signalling receptors to control cell fate in many developmental and adult tissue contexts. Notch signalling continues to be important in the adult organism for tissue maintenance and renewal and mis-regulation of Notch is involved in many diseases. Genetic studies have shown that gene knockouts are viable and have limited developmental defects, focussed mostly on defects in the arterial smooth muscle cell lineage. Additional studies have revealed overlapping roles for Notch3 with other Notch proteins, which widen the range of developmental functions. In the adult, Notch3, in collaboration with other Notch proteins, is involved in stem cell regulation in different tissues in stem cell regulation in different tissues, and it also controls the plasticity of the vascular smooth muscle phenotype involved in arterial vessel remodelling. Overexpression, gene amplification and mis-activation of Notch3 are associated with different cancers, in particular triple negative breast cancer and ovarian cancer. Mutations of Notch3 are associated with a dominantly inherited disease CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy), and there is further evidence linking Notch3 misregulation to hypertensive disease. Here we discuss the distinctive roles of Notch3 in development, health and disease, different views as to the underlying mechanisms of its activation and misregulation in different contexts and potential for therapeutic intervention.
Notch3 是四种哺乳动物 Notch 蛋白之一，作为信号受体在许多发育和成人组织环境中控制细胞命运。Notch 信号在成年生物体中对于组织维持和更新仍然很重要， Notch 的失调与许多疾病有关。遗传研究表明， Notch3 基因敲除是可行的，并且发育缺陷有限，主要集中在动脉平滑肌细胞谱系的缺陷上。其他研究表明 Notch3 与其他 Notch 蛋白具有重叠作用，这拓宽了发育功能的范围。在成年期， Notch3 与其他 Notch 蛋白一起参与不同组织的干细胞调节，也控制参与动脉血管重塑的血管平滑肌表型的可塑性。 Notch3 的过表达、基因扩增和异常激活与不同的癌症有关，特别是三阴性乳腺癌和卵巢癌。 Notch3 的突变与一种常染色体显性遗传疾病 CADASIL（伴有皮质下梗死和白质脑病的脑常染色体显性动脉病）有关，还有进一步的证据表明 Notch3 的失调与高血压疾病有关。在这里，我们讨论了 Notch3 在发育、健康和疾病中的独特作用，以及不同背景下其激活和失调的潜在机制和治疗干预的可能性。
