Madelaine Romain, Sloan Steven A, Huber Nina, Notwell James H, Leung Louis C, Skariah Gemini, Halluin Caroline, Paşca Sergiu P, Bejerano Gill, Krasnow Mark A, Barres Ben A, Mourrain Philippe
Stanford Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA.
Department of Neurobiology, Stanford University, Stanford, CA 94305, USA.
Cell Rep. 2017 Aug 15;20(7):1533-1542. doi: 10.1016/j.celrep.2017.07.051.
In the developing brain, neurons expressing VEGF-A and blood vessels grow in close apposition, but many of the molecular pathways regulating neuronal VEGF-A and neurovascular system development remain to be deciphered. Here, we show that miR-9 links neurogenesis and angiogenesis through the formation of neurons expressing VEGF-A. We found that miR-9 directly targets the transcription factors TLX and ONECUTs to regulate VEGF-A expression. miR-9 inhibition leads to increased TLX and ONECUT expression, resulting in VEGF-A overexpression. This untimely increase of neuronal VEGF-A signal leads to the thickening of blood vessels at the expense of the normal formation of the neurovascular network in the brain and retina. Thus, this conserved transcriptional cascade is critical for proper brain development in vertebrates. Because of this dual role on neural stem cell proliferation and angiogenesis, miR-9 and its downstream targets are promising factors for cellular regenerative therapy following stroke and for brain tumor treatment.
在发育中的大脑中，表达血管内皮生长因子A（VEGF-A）的神经元与血管紧密相邻生长，但许多调节神经元VEGF-A和神经血管系统发育的分子途径仍有待阐明。在此，我们表明miR-9通过形成表达VEGF-A的神经元来连接神经发生和血管生成。我们发现miR-9直接靶向转录因子TLX和ONECUTs以调节VEGF-A的表达。miR-9抑制导致TLX和ONECUT表达增加，从而导致VEGF-A过表达。神经元VEGF-A信号的这种过早增加导致血管增厚，却以牺牲大脑和视网膜中神经血管网络的正常形成为代价。因此，这种保守的转录级联反应对于脊椎动物正常的大脑发育至关重要。由于miR-9对神经干细胞增殖和血管生成具有双重作用，miR-9及其下游靶点有望成为中风后细胞再生治疗和脑肿瘤治疗的重要因素。
