Single-cell analysis of the ventricular-subventricular zone reveals signatures of dorsal and ventral adult neurogenesis.
Single-cell analysis of the ventricular-subventricular zone reveals signatures of dorsal and ventral adult neurogenesis.
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DOI：
10.7554/elife.67436
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发表时间：
2021-07-14
期刊：
影响因子：
7.7
通讯作者：
Álvarez-Buylla A
中科院分区：
文献类型：
--
作者：
Cebrian-Silla A;Nascimento MA;Redmond SA;Mansky B;Wu D;Obernier K;Romero Rodriguez R;Gonzalez-Granero S;García-Verdugo JM;Lim DA;Álvarez-Buylla A
侧脑室壁上的心室-室下区（V-SVZ）是成年小鼠大脑中最大的神经源性生态位。先前的研究表明，位于V-SVZ内不同位置的神经干/祖细胞（NSPCs）为嗅球产生不同亚型的新神经元。这种区域异质性背后的分子特征在很大程度上仍然未知。在这里，我们展示了成年小鼠V-SVZ的单细胞rna测序数据集，揭示了两个位于V-SVZ背侧或腹侧大部分不重叠区域的NSPCs群体。利用V-SVZ区域微解剖结构域的单核rna测序参考数据集以及免疫细胞化学和RNAscope定位，进一步验证了这些基因表达的区域差异。我们还确定了两个亚群的年轻神经元，其基因表达谱与背侧或腹侧起源一致。有趣的是，在腹侧或背侧谱系中，有一部分基因是动态表达的，但却得以维持。该研究为了解成人神经发生的区域特异性调节提供了新的标记和领域。神经细胞或神经元是大脑回路的核心组成部分。它们的损伤、死亡或功能丧失会导致认知能力下降。神经干细胞/祖细胞（NSPCs）在胚胎发育过程中首次出现，产生了神经系统中发现的大多数神经元。然而，成人大脑中保留了一小部分NSPCs亚群，在某些物种中，NSPCs是整个生命中新神经元的重要来源。在成年小鼠的大脑中，被称为B细胞的NSPCs数量最多的区域是心室-室下区（V-SVZ）。这些V-SVZ B细胞具有被称为星形胶质细胞的特殊支持细胞的特性，但它们也可以分裂并产生称为C细胞的中间“祖细胞”。这些细胞依次分裂产生大量年轻的“A细胞”神经元，从V-SVZ向嗅球进行漫长而复杂的迁移，嗅球是中枢神经系统中处理气味的第一个中继。根据它们在V-SVZ中的位置，B细胞可以产生不同种类的神经元，导致至少十种亚型的神经元。为什么会出现这种情况，人们仍然知之甚少。为了研究这个问题，Cebrián-Silla、Nascimento、Redmond、Mansky等人确定了哪些基因在V-SVZ不同部位的B、C和A细胞中表达。虽然这些群体中的每个细胞都有不同的表达模式，但那些起源于相同V-SVZ位置的细胞共享一组基因，其中许多基因与发育中的大脑区域规范有关。然而，有趣的是，其中一些与荷尔蒙调节有关。B细胞之间的显著差异取决于细胞是起源于更靠近大脑顶部（“背侧”位置）还是更靠近大脑底部（“腹侧”位置）。这些信息被用于对小鼠大脑切片进行染色，以检测这些基因在不同区域产生的RNA和蛋白质。这些实验揭示了背侧和腹侧区域含有具有不同“基因表达”的B细胞。该研究强调了NSPCs的异质性，揭示了V-SVZ背侧和腹侧区域B细胞之间的关键分子差异，并强化了NSPCs的位置决定其产生的神经元类型的概念。此外，来自B细胞的特定类型神经元的诞生是如此严格地定位，突出了神经元迁移的重要性，以确保具有特定特性的年轻神经元到达嗅球中的适当目的地。Cebrián-Silla, Nascimento, Redmond， Mansky等人的工作已经确定了在背侧和腹侧区域差异表达的一系列基因，这些基因可能有助于区域调节。进一步了解成人非spcs如何根据其位置而有所不同，将有助于确定各种神经元类型如何在成人大脑中出现。
The ventricular-subventricular zone (V-SVZ), on the walls of the lateral ventricles, harbors the largest neurogenic niche in the adult mouse brain. Previous work has shown that neural stem/progenitor cells (NSPCs) in different locations within the V-SVZ produce different subtypes of new neurons for the olfactory bulb. The molecular signatures that underlie this regional heterogeneity remain largely unknown. Here, we present a single-cell RNA-sequencing dataset of the adult mouse V-SVZ revealing two populations of NSPCs that reside in largely non-overlapping domains in either the dorsal or ventral V-SVZ. These regional differences in gene expression were further validated using a single-nucleus RNA-sequencing reference dataset of regionally microdissected domains of the V-SVZ and by immunocytochemistry and RNAscope localization. We also identify two subpopulations of young neurons that have gene expression profiles consistent with a dorsal or ventral origin. Interestingly, a subset of genes are dynamically expressed, but maintained, in the ventral or dorsal lineages. The study provides novel markers and territories to understand the region-specific regulation of adult neurogenesis. Nerve cells, or neurons, are the central building blocks of brain circuits. Their damage, death or loss of function leads to cognitive decline. Neural stem/progenitor cells (NSPCs) first appear during embryo development, generating most of the neurons found in the nervous system. However, the adult brain retains a small subpopulation of NSPCs, which in some species are an important source of new neurons throughout life. In the adult mouse brain the largest population of NSPCs, known as B cells, is found in an area called the ventricular-subventricular zone (V-SVZ). These V-SVZ B cells have properties of specialized support cells known as astrocytes, but they can also divide and generate intermediate ‘progenitor cells’ called C cells. These, in turn, divide to generate large numbers of young ‘A cells’ neurons that undertake a long and complex migration from V-SVZ to the olfactory bulb, the first relay in the central nervous system for the processing of smells. Depending on their location in the V-SVZ, B cells can generate different kinds of neurons, leading to at least ten subtypes of neurons. Why this is the case is still poorly understood. To examine this question, Cebrián-Silla, Nascimento, Redmond, Mansky et al. determined which genes were expressed in B, C and A cells from different parts of the V-SVZ. While cells within each of these populations had different expression patterns, those that originated in the same V-SVZ locations shared a set of genes, many of which associated with regional specification in the developing brain. Some, however, were intriguingly linked to hormonal regulation. Salient differences between B cells depended on whether the cells originated closer to the top (‘dorsal’ position) or to the bottom of the brain (‘ventral’ position). This information was used to stain slices of mouse brains for the RNA and proteins produced by these genes in different regions. These experiments revealed dorsal and ventral territories containing B cells with distinct ‘gene expression’. This study highlights the heterogeneity of NSPCs, revealing key molecular differences among B cells in dorsal and ventral areas of the V-SVZ and reinforcing the concept that the location of NSPCs determines the types of neuron they generate. Furthermore, the birth of specific types of neurons from B cells that are so strictly localized highlights the importance of neuronal migration to ensure that young neurons with specific properties reach their appropriate destination in the olfactory bulb. The work by Cebrián-Silla, Nascimento, Redmond, Mansky et al. has identified sets of genes that are differentially expressed in dorsal and ventral regions which may contribute to regional regulation. Furthering the understanding of how adult NSPCs differ according to their location will help determine how various neuron types emerge in the adult brain.