Single-cell transcriptomic analysis identifies neocortical developmental differences between human and mouse

Abstract

20Background: The specification and differentiation of neocortical projection neurons is a 21complex process under precise molecular regulation; however, little is known about the 22 similarities and differences in cerebral cortex development between human and mouse at 23 single-cell resolution. 24Results: Here, using single-cell RNA-seq (scRNA-seq) data we explore the divergence 25 and conservation of human and mouse cerebral cortex development using 18,446 and 26 7,610 neocortical cells. Systematic cross-species comparison reveals that the overall 27 transcriptome profile in human cerebral cortex is similar to that in mouse such as cell types 28 and their markers genes. By single-cell trajectories analysis we find human and mouse 29 excitatory neurons have different developmental trajectories of neocortical projection 30 neurons, ligand-receptor interactions and gene expression patterns. Further analysis 31 reveals a refinement of neuron differentiation that occurred in human but not in mouse, 32suggesting that excitatory neurons in human undergo refined transcriptional states in later 33 development stage. By contrast, for glial cells and inhibitory neurons we detected 34 conserved developmental trajectories in human and mouse. 35 Conclusions: Taken together, our study integrates scRNA-seq data of cerebral cortex 36 development in human and mouse, and uncovers distinct developing models in 37 neocortical projection neurons. The earlier activation of cognition -related genes in human 38 may explain the differences in behavior, learning or memory abilities between the two 39 species. 40 41 Cognition 44 45 46 3 Background 47The mammalian cerebral cortex develops via a complex process of cell proliferation, 48 differentiation, and migration events. The molecular features of the human brain at 49 gestational weeks 7-23 are similar to those of the mouse at postnatal days 14.5 to birth 50 (P0) and reveal gene expression differences between the two species [1, 2]. Interneurons 51 and projection neurons, which are the two major classes of neurons, populate the 52 neocortex. Interneurons show largely GABAergic, connecting locally within the neocortex, 53 and are generated by progenitors in the ventral telencephalic (inhibitory cortical 54 interneuron producing) radial glia, before migrating from sub pallial ganglionic eminences 55 into the cortex [3][4][5][6]. By contrast, projection neurons are excitatory, which are generated 56 by progenitors in the dorsal telencephalic (excitatory cortical neuron producing) radial glia 57 [7][8][9]. 58 59Despite immense efforts over the past decades to study the cell types, function, 60 differentiation for the mammalian cerebral cortex, especially human and mouse, large 61 differences and conservation are observed in human versus animal models [10][11][12]. 62Elucidating the conserved, divergent and cellular architecture of developing the cerebral 63 cortex, especially projection neurons developments, may highlight to understanding 64 susceptibility to neurological diseases and the o...