Comparative cellular analysis of motor cortex in human, marmoset and mouse

TLDR

The primary motor cortex (M1) is essential for voluntary fine‑motor control and is functionally conserved across mammals. The study aims to use a consensus transcriptomic classification to identify corticospinal Betz cells in non‑human primates and humans and to characterize their specialized physiology and anatomy. The authors performed high‑throughput single‑nucleus transcriptomic and epigenomic profiling of over 450,000 nuclei from humans, marmosets, and mice, and applied patch‑seq to the identified Betz cells. They found a broadly conserved cellular makeup that mirrors evolutionary distance, established a cross‑species consensus classification of neuronal and non‑neuronal cell types, revealed species‑dependent specializations in cell‑type proportions and epigenetic states, identified a limited set of conserved marker genes such as those for GABAergic chandelier cells, and highlighted genes and regulatory pathways that underlie functional identity and species‑specific adaptations.

Abstract

Abstract The primary motor cortex (M1) is essential for voluntary fine-motor control and is functionally conserved across mammals 1 . Here, using high-throughput transcriptomic and epigenomic profiling of more than 450,000 single nuclei in humans, marmoset monkeys and mice, we demonstrate a broadly conserved cellular makeup of this region, with similarities that mirror evolutionary distance and are consistent between the transcriptome and epigenome. The core conserved molecular identities of neuronal and non-neuronal cell types allow us to generate a cross-species consensus classification of cell types, and to infer conserved properties of cell types across species. Despite the overall conservation, however, many species-dependent specializations are apparent, including differences in cell-type proportions, gene expression, DNA methylation and chromatin state. Few cell-type marker genes are conserved across species, revealing a short list of candidate genes and regulatory mechanisms that are responsible for conserved features of homologous cell types, such as the GABAergic chandelier cells. This consensus transcriptomic classification allows us to use patch–seq (a combination of whole-cell patch-clamp recordings, RNA sequencing and morphological characterization) to identify corticospinal Betz cells from layer 5 in non-human primates and humans, and to characterize their highly specialized physiology and anatomy. These findings highlight the robust molecular underpinnings of cell-type diversity in M1 across mammals, and point to the genes and regulatory pathways responsible for the functional identity of cell types and their species-specific adaptations.