Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
Nature. 2024 May;629(8011):384-392. doi: 10.1038/s41586-024-07292-5. Epub 2024 Apr 10.
Debate remains around the anatomical origins of specific brain cell subtypes and lineage relationships within the human forebrain. Thus, direct observation in the mature human brain is critical for a complete understanding of its structural organization and cellular origins. Here we utilize brain mosaic variation within specific cell types as distinct indicators for clonal dynamics, denoted as cell-type-specific mosaic variant barcode analysis. From four hemispheres and two different human neurotypical donors, we identified 287 and 780 mosaic variants, respectively, that were used to deconvolve clonal dynamics. Clonal spread and allele fractions within the brain reveal that local hippocampal excitatory neurons are more lineage-restricted than resident neocortical excitatory neurons or resident basal ganglia GABAergic inhibitory neurons. Furthermore, simultaneous genome transcriptome analysis at both a cell-type-specific and a single-cell level suggests a dorsal neocortical origin for a subgroup of DLX1 inhibitory neurons that disperse radially from an origin shared with excitatory neurons. Finally, the distribution of mosaic variants across 17 locations within one parietal lobe reveals that restriction of clonal spread in the anterior-posterior axis precedes restriction in the dorsal-ventral axis for both excitatory and inhibitory neurons. Thus, cell-type-resolved somatic mosaicism can uncover lineage relationships governing the development of the human forebrain.
关于特定脑细胞亚型在人类前脑中的解剖学起源以及谱系关系仍存在争议。因此，直接观察成熟人脑对于全面了解其结构组织和细胞起源至关重要。在这里，我们利用特定细胞类型内的脑镶嵌变体作为克隆动力学的独特指标，称为细胞类型特异性镶嵌变体条码分析。我们从四个半球和两个不同的人类神经典型供体中分别鉴定出 287 和 780 个镶嵌变体，这些变体用于推断克隆动力学。大脑内的克隆扩散和等位基因分数表明，局部海马兴奋性神经元比驻留的新皮层兴奋性神经元或驻留的基底节 GABA 能抑制性神经元的谱系限制更大。此外，在细胞类型特异性和单细胞水平上的同时基因组转录组分析表明，一组 DLX1 抑制性神经元具有背侧新皮层起源，它们从与兴奋性神经元共享的起源处呈放射状扩散。最后，在一个顶叶叶内的 17 个位置上的镶嵌变体的分布表明，无论是兴奋性神经元还是抑制性神经元，前后轴上的克隆扩散限制都先于背腹轴上的限制。因此，细胞类型分辨的体突变体可以揭示控制人类前脑发育的谱系关系。
