北京昌平实验室Qian Wu，中国科学院生物物理研究所Xiaoqun Wang和广东省智能科学技术研究院Yingchao Shi共同合作，近期取得重要工作进展。他们研究解码人类脊髓发育过程中转录因子的时空调控。相关研究成果2024年1月5日在线发表于《细胞研究》杂志上。

据介绍，脊髓是中枢神经系统的重要组成部分，有助于感觉处理和运动表现。尽管它很重要，但人类脊髓发育的时空密码仍然难以捉摸。

研究人员引入了一种基于图像的单细胞转录因子（TF）表达解码空间转录组方法（TF-seqFISH），来研究TF在人类脊髓发育过程中的空间表达和调节。通过结合TF-seqFISH的空间转录组数据和单细胞RNA测序数据，研究人员揭示了以组合TF为特征的神经祖细胞沿背腹轴的空间分布，以及控制神经元沿中横轴产生、迁移和分化的分子和空间特征。研究人员观察到兴奋性和抑制性中间神经元的三明治状组织，短暂出现在发育中的人类脊髓的背角。

此外，研究人员整合了10xvisium的数据，确定了背角神经发生的早期和晚期波，揭示了背角椎板的形成。这一研究还阐明了运动神经元（MN）多样化的空间差异和分子线索，以及肌萎缩侧索硬化症（ALS）风险基因在MN和小胶质细胞中的富集。研究人员在发育中的人类脊髓中检测到了与疾病相关的小胶质细胞（DAM）样细胞群，这些小胶质细胞被预测易受ALS的影响，并参与TYROBP因果网络和对未折叠蛋白的反应。

附：英文原文

Title: Decoding the spatiotemporal regulation of transcription factors during human spinal cord development

Author: Shi, Yingchao, Huang, Luwei, Dong, Hao, Yang, Meng, Ding, Wenyu, Zhou, Xiang, Lu, Tian, Liu, Zeyuan, Zhou, Xin, Wang, Mengdi, Zeng, Bo, Sun, Yinuo, Zhong, Suijuan, Wang, Bosong, Wang, Wei, Yin, Chonghai, Wang, Xiaoqun, Wu, Qian

Issue&Volume: 2024-01-05

Abstract: The spinal cord is a crucial component of the central nervous system that facilitates sensory processing and motor performance. Despite its importance, the spatiotemporal codes underlying human spinal cord development have remained elusive. In this study, we have introduced an image-based single-cell transcription factor (TF) expression decoding spatial transcriptome method (TF-seqFISH) to investigate the spatial expression and regulation of TFs during human spinal cord development. By combining spatial transcriptomic data from TF-seqFISH and single-cell RNA-sequencing data, we uncovered the spatial distribution of neural progenitor cells characterized by combinatorial TFs along the dorsoventral axis, as well as the molecular and spatial features governing neuronal generation, migration, and differentiation along the mediolateral axis. Notably, we observed a sandwich-like organization of excitatory and inhibitory interneurons transiently appearing in the dorsal horns of the developing human spinal cord. In addition, we integrated data from 10×Visium to identify early and late waves of neurogenesis in the dorsal horn, revealing the formation of laminas in the dorsal horns. Our study also illuminated the spatial differences and molecular cues underlying motor neuron (MN) diversification, and the enrichment of Amyotrophic Lateral Sclerosis (ALS) risk genes in MNs and microglia. Interestingly, we detected disease-associated microglia (DAM)-like microglia groups in the developing human spinal cord, which are predicted to be vulnerable to ALS and engaged in the TYROBP causal network and response to unfolded proteins. These findings provide spatiotemporal transcriptomic resources on the developing human spinal cord and potential strategies for spinal cord injury repair and ALS treatment.

DOI: 10.1038/s41422-023-00897-x

Source: https://www.nature.com/articles/s41422-023-00897-x