论文
论文标题：Genetic and epigenetic coordination of cortical interneuron development
作者：Allaway, Kathryn C., Gabitto, Mariano I., Wapinski, Orly, Saldi, Giuseppe, Wang, Chen-Yu, Bandler, Rachel C., Wu, Sherry Jingjing, Bonneau, Richard, Fishell, Gord
期刊：Nature
发表时间：2021/09/22
数字识别码：10.1038/s41586-021-03933-1
摘要：One of the hallmarks of the cerebral cortex is the extreme diversity of interneurons1,2,3. The two largest subtypes of cortical interneurons, parvalbumin- and somatostatin-positive cells, are morphologically and functionally distinct in adulthood but arise from common lineages within the medial ganglionic eminence4,5,6,7,8,9,10,11. This makes them an attractive model for studying the generation of cell diversity. Here we examine how developmental changes in transcription and chromatin structure enable these cells to acquire distinct identities in the mouse cortex. Generic interneuron features are first detected upon cell cycle exit through the opening of chromatin at distal elements. By constructing cell-type-specific gene regulatory networks, we observed that parvalbumin- and somatostatin-positive cells initiate distinct programs upon settling within the cortex. We used these networks to model the differential transcriptional requirement of a shared regulator, Mef2c, and confirmed the accuracy of our predictions through experimental loss-of-function experiments. We therefore reveal how a common molecular program diverges to enable these neuronal subtypes to acquire highly specialized properties by adulthood. Our methods provide a framework for examining the emergence of cellular diversity, as well as for quantifying and predicting the effect of candidate genes on cell-type-specific development.
近日，美国哈佛大学医学院Gord Fishell研究组与Flatiron研究所Richard Bonneau研究组合作发文题为Genetic and epigenetic coordination of cortical interneuron development，通过对大脑皮层中PV细胞以及SST细胞发育以及分化过程中遗传学以及表观遗传景观的绘制揭开了皮层中间神经元发育的神经调控网络并对其中关键的转录因子的作用机制进行了解析。
为了对PV细胞以及SST细胞的特异性分歧进行解析，作者们先前的研究发现在转录水平上，中间神经元分成三个分支，其中一个分支对应中间神经元前体细胞，另外两个分支对应投射神经元前体细胞【4】。为了对中间神经元多样性的具体机制进行解释，作者们对比了胚胎时期E13天这些分支前体细胞的RNA表达以及染色质可及性，这一时期正是内侧神经节隆起（Medial ganglionic eminence，MGE）中间神经元发生的高峰阶段。作者们使用单细胞RNA测序、ATAC-seq（Assay for transposase-accessible chromatin with sequencing）测序以及多组学联用等测序方式对报告转基因小鼠的E13天的MGE中间神经元前体细胞进行检测。通过将多组学的结果进行吻合比对，作者们发现，与基因表达相比发育相关基因的启动子可及性的出现通常更早且维持时间更久。
1 Ascoli, G. A. et al. Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex. Nature reviews. Neuroscience 9, 557-568, doi:10.1038/nrn2402 (2008).
2 DeFelipe, J. et al. New insights into the classification and nomenclature of cortical GABAergic interneurons. Nature reviews. Neuroscience 14, 202-216, doi:10.1038/nrn3444 (2013).
3 Kepecs, A. & Fishell, G. Interneuron cell types are fit to function. Nature 505, 318-326, doi:10.1038/nature12983 (2014).
4 Mayer, C. et al. Developmental diversification of cortical inhibitory interneurons. Nature 555, 457-462, doi:10.1038/nature25999 (2018).
5 Pai, E. L. et al. Mafb and c-Maf Have Prenatal Compensatory and Postnatal Antagonistic Roles in Cortical Interneuron Fate and Function. Cell reports 26, 1157-1173.e1155, doi:10.1016/j.celrep.2019.01.031 (2019).
