Temporal controls over inter-areal cortical projection neuron fate diversity
Temporal controls over inter-areal cortical projection neuron fate diversity
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DOI：
10.1038/s41586-021-04048-3
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发表时间：
2021-11-09
期刊：
影响因子：
64.8
通讯作者：
Jabaudon, Denis
中科院分区：
文献类型：
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作者：
Klingler, Esther;Tomasello, Ugo;Jabaudon, Denis
新皮质区域之间的相互连接对于感觉整合和感觉运动转换至关重要(1-6)。这些功能是由异质皮质间皮质投射神经元(ICPN)介导的，它将轴突分支发送到皮质区域以及皮质下靶点(7-9)。尽管ICPN在解剖学上是多样化的(10-14)，但它们在分子上是同质的(15)，它们在发育过程中解剖和功能特征的多样性如何出现在很大程度上仍不清楚。在这里，我们通过将小鼠新皮质单个ICPN的形成过程中的连接体和转录组联系起来，使用通过测序(16，17)(MAPseq，以识别单个神经元轴突投射)和单细胞RNA测序(以识别相应的基因表达)的多重投影分析相结合的方法来解决这个问题。以初级躯体感觉皮层(S1)神经元为研究对象，揭示了运动皮质投射((M))ICPN与次级躯体感觉皮质(S2)投射(S2)ICPN的分子和功能分化的长期展开过程。我们确定sox11是一个时间差异表达的转录因子，在右箭头ICPN上的(M)和右箭头ICPN上的(S2)中。出生后操纵s1中sox11的表达会损害小鼠感觉运动的连通性，并扰乱小鼠的选择性探索行为。综上所述，我们的结果表明，在单个皮质区域内，不同亚型的ICPN具有不同的出生后分子分化步伐，这随后反映在不同的电路连接性和功能上。因此，大体上通用的一组基因表达水平的动态差异，而不是发育遗传程序同一性的根本差异，可能是皮质神经元出现内型多样性的原因。
Interconnectivity between neocortical areas is critical for sensory integration and sensorimotor transformations(1-6). These functions are mediated by heterogeneous inter-areal cortical projection neurons (ICPN), which send axon branches across cortical areas as well as to subcortical targets(7-9). Although ICPN are anatomically diverse(10-14), they are molecularly homogeneous(15), and how the diversity of their anatomical and functional features emerge during development remains largely unknown. Here we address this question by linking the connectome and transcriptome in developing single ICPN of the mouse neocortex using a combination of multiplexed analysis of projections by sequencing(16,17) (MAPseq, to identify single-neuron axonal projections) and single-cell RNA sequencing (to identify corresponding gene expression). Focusing on neurons of the primary somatosensory cortex (S1), we reveal a protracted unfolding of the molecular and functional differentiation of motor cortex-projecting ((M) over right arrow) ICPN compared with secondary somatosensory cortex-projecting ((S2) over right arrow) ICPN. We identify SOX11 as a temporally differentially expressed transcription factor in (M) over right arrow versus (S2) over right arrow ICPN. Postnatal manipulation of SOX11 expression in S1 impaired sensorimotor connectivity and disrupted selective exploratory behaviours in mice. Together, our results reveal that within a single cortical area, different subtypes of ICPN have distinct postnatal paces of molecular differentiation, which are subsequently reflected in distinct circuit connectivities and functions. Dynamic differences in the expression levels of a largely generic set of genes, rather than fundamental differences in the identity of developmental genetic programs, may thus account for the emergence of intra-type diversity in cortical neurons.