Wang Tao, Baron Martin, Trump Dorothy
Medical Genetics Research Group and Centre for Molecular Medicine, School of Clinical and Laboratory Sciences, Faculty of Medicine and Human Sciences, The University of Manchester, UK.
Prog Biophys Mol Biol. 2008 Jan-Apr;96(1-3):499-509. doi: 10.1016/j.pbiomolbio.2007.07.006. Epub 2007 Jul 29.
Proteins of the Notch family are cell surface receptors that transduce signals between neighbouring cells. The Notch signalling pathway is highly evolutionarily conserved and critical for cell fate determination during embryonic development, including many aspects of vascular development. The interaction of Notch receptors with ligands leads to cleavage of the Notch intracellular domain (NICD) which then translocates to the nucleus and activates the transcription factor CBF1/JBP-Jkappa, regulating downstream gene expression. To date four Notch receptors have been found in mammals. Of these, Notch3 is predominantly expressed in adult arterial smooth muscle cells in human. NOTCH3 gene mutations cause the autosomal dominant condition, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoecephelopathy (CADASIL), an inherited early stroke syndrome leading to dementia due to systemic vascular degeneration. This suggests that Notch3 plays a critical role in maintaining the phenotypic stability of vascular smooth muscle cells (VSMCs). Recent publications indicate that Notch3 is involved in vascular injury and is a determinant of VSMC survival, but its exact function is unknown. The molecular mechanisms underlying CADASIL pathology are therefore intriguing. Investigation of CADASIL mutant Notch3 shows that the majority of mutations do not change CBF1/JBP-Jkappa mediated classic Notch activation, so the pathological consequences of NOTCH3 mutations in CADASIL patients can not be simply explained by loss- or gain-of-function in the classic Notch signalling pathway. This suggests that a novel Notch3-mediated signalling pathway may be present in VSMCs, or cross-regulation of Notch3 to other signalling pathway(s) may play a critical role on VSMCs survival. Alternatively, the mutant Notch3 may gain a novel or toxic function in VSMCs. This review will focus on recent findings of Notch3 in vascular development and in regulating the VSMC behaviour and phenotype, and will use findings on investigating the molecular pathology of the single gene disorder CADASIL to understand the function of Notch3 in VSMCs.
Notch家族蛋白是细胞表面受体，可在相邻细胞间传导信号。Notch信号通路在进化上高度保守，对胚胎发育过程中的细胞命运决定至关重要，包括血管发育的许多方面。Notch受体与配体的相互作用导致Notch细胞内结构域（NICD）的切割，然后NICD转移至细胞核并激活转录因子CBF1/JBP-Jkappa，从而调节下游基因表达。迄今为止，在哺乳动物中已发现四种Notch受体。其中，Notch3主要在人类成年动脉平滑肌细胞中表达。NOTCH3基因突变会导致常染色体显性疾病——伴有皮质下梗死和白质脑病的大脑常染色体显性动脉病（CADASIL），这是一种遗传性早期中风综合征，由于系统性血管退变可导致痴呆。这表明Notch3在维持血管平滑肌细胞（VSMC）的表型稳定性中起关键作用。最近的出版物表明，Notch3参与血管损伤，是VSMC存活的决定因素，但其确切功能尚不清楚。因此，CADASIL病理的分子机制很有趣。对CADASIL突变型Notch3的研究表明，大多数突变不会改变CBF1/JBP-Jkappa介导的经典Notch激活，因此CADASIL患者中NOTCH3突变的病理后果不能简单地用经典Notch信号通路的功能丧失或获得来解释。这表明在VSMC中可能存在一种新的Notch3介导的信号通路，或者Notch3对其他信号通路的交叉调节可能在VSMC存活中起关键作用。或者，突变型Notch3可能在VSMC中获得新的或有毒的功能。本综述将聚焦于Notch3在血管发育以及调节VSMC行为和表型方面的最新研究发现，并将利用对单基因疾病CADASIL分子病理学的研究结果来理解Notch3在VSMC中的功能。
