Pharmacogenomic identification of small molecules for lineage specific manipulation of subventricular zone germinal activity.
Pharmacogenomic identification of small molecules for lineage specific manipulation of subventricular zone germinal activity.
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DOI：
10.1371/journal.pbio.2000698
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发表时间：
2017-03
期刊：
影响因子：
9.8
通讯作者：
Raineteau O
中科院分区：
文献类型：
--
作者：
Azim K;Angonin D;Marcy G;Pieropan F;Rivera A;Donega V;Cantù C;Williams G;Berninger B;Butt AM;Raineteau O
促进神经再生的策略受到阻碍，因为如果没有复杂的遗传方法，很难操纵大脑中所需的神经命运。室管膜下区（SVZ）是前脑最大的生发区，负责中间神经元亚型和少突胶质细胞的终身生成。在这里，我们已经进行了生物信息学分析的背侧和侧SVZ在出生后早期小鼠，包括神经干细胞（NSC）及其直接后代，产生不同的神经谱系的转录组。我们确定了多种信号通路，触发不同的下游转录网络，以调节起源于SVZ的神经细胞的多样性。接下来，我们使用了一种新的计算机基因组分析，可搜索的平台无关的表达数据库/连接图（SPIED/CMAP），以生成一个可用于操纵SVZ微域特异性谱系的小分子目录。最后，我们证明了在这种分析中确定的化合物促进特定的细胞谱系的生成从神经干细胞在体内，在出生后的生活和成年，以及在再生的背景下。这项研究揭示了使用小的生物活性分子来指导SVZ中的生发活性的新策略，这在神经退行性疾病中具有治疗潜力。室管膜下区是出生后和成人脑中最大的发育区。它含有神经干细胞（NSC），以区域特异性方式产生神经元和少突胶质细胞（OL）。在这里，我们使用生物信息学的方法来确定多种信号通路，调节细胞谱系的多样性，起源于不同的SVZ亚区。我们进一步使用基于计算的药物发现策略来识别可用于操纵SVZ区域化的小分子目录。我们提供的证据表明，通过在体内给药的小分子，它是可能的，以促进特定的生成的神经元和神经干细胞在出生后和成人的大脑，以及在损伤后的再生环境。这项研究揭示了新的策略，使用小的生物活性分子直接在SVZ，这在神经退行性疾病的治疗潜力的生发活性。
Strategies for promoting neural regeneration are hindered by the difficulty of manipulating desired neural fates in the brain without complex genetic methods. The subventricular zone (SVZ) is the largest germinal zone of the forebrain and is responsible for the lifelong generation of interneuron subtypes and oligodendrocytes. Here, we have performed a bioinformatics analysis of the transcriptome of dorsal and lateral SVZ in early postnatal mice, including neural stem cells (NSCs) and their immediate progenies, which generate distinct neural lineages. We identified multiple signaling pathways that trigger distinct downstream transcriptional networks to regulate the diversity of neural cells originating from the SVZ. Next, we used a novel in silico genomic analysis, searchable platform-independent expression database/connectivity map (SPIED/CMAP), to generate a catalogue of small molecules that can be used to manipulate SVZ microdomain-specific lineages. Finally, we demonstrate that compounds identified in this analysis promote the generation of specific cell lineages from NSCs in vivo, during postnatal life and adulthood, as well as in regenerative contexts. This study unravels new strategies for using small bioactive molecules to direct germinal activity in the SVZ, which has therapeutic potential in neurodegenerative diseases. The subventricular zone (SVZ) is the largest germinal zone of the postnatal and adult brain. It contains neural stem cells (NSCs) that give rise to neurons and oligodendrocytes (OLs) in a region-specific manner. Here, we use a bioinformatics approach to identify multiple signaling pathways that regulate the diversity of cell lineages that originate from different subregions of the SVZ. We further use a computational-based drug-discovery strategy to identify a catalogue of small molecules that can be used to manipulate the regionalization of the SVZ. We provide proof that, by administration of small molecules in vivo, it is possible to promote the specific generation of neurons and OLs from NSCs in both the postnatal and adult brain, as well as in regenerative contexts after lesion. This study unravels novel strategies for using small bioactive molecules to direct germinal activity in the SVZ, which has therapeutic potential in neurodegenerative diseases.