Biology subjects

Sheu, X. D.

Publications and source records attributed to Sheu, X. D..

3 recordsLinked to original sources

bioRxiv2026

Coupled transcriptomic divergence establishes a human-specific synaptic glial precursor state

The mammalian cerebral cortex is built from a conserved developmental program, yet exhibits profound species-specific complexity. To decode the regulatory changes driving human brain evolution, we reconstructed and aligned continuous single-cell differentiation trajectories across the developing human, macaque, mouse, and ferret cortices. This comparative framework revealed a fundamental principle of transcriptomic evolution during mammalian cortical development: while stable expression is the mammalian default, genes that diverge strictly shift their allocation to cell differentiation trajectories and developmental timing in tandem. By isolating these coupled regulatory shifts to the human lineage, we revealed that a canonical synaptic gene network uniquely redeployed into early human oligodendrocyte precursor cells (OPCs). Human, chimpanzee, and gorilla cortical organoids confirmed that this neuron-like OPC state is an exclusively human innovation. Spatial transcriptome analysis found that these specialized OPCs engage adjacent neural progenitors (outer radial glia) via synaptic-adhesion signaling during neurogenetic period. These findings demonstrate that this coupled spatiotemporal rewiring establishes novel developmental microenvironments, providing a discrete molecular engine for human cortical evolution.

genomics↗

bioRxiv2025

Human-specific NOTCH2NL promotes astrogenesis by expanding proliferative glial progenitor states

The human cerebral cortex contains an unusually large number of glial cells, particularly astrocytes, yet the developmental and genetic mechanisms underlying their expansion remain poorly understood. While human-specific genes have been shown to promote neuronal production during cortical development, whether such genes also regulate gliogenesis has remained unclear. Here, we identify a previously unrecognized role for the human-specific gene family NOTCH2NL in promoting astrocyte-lineage expansion. Reanalysis of human fetal single-cell transcriptomic datasets revealed that NOTCH2NL is robustly expressed along the gliogenic trajectory, from glial intermediate progenitor cells to astrocytes. Functional perturbations in a human astrocyte culture system demonstrated that NOTCH2NL is both required and sufficient for astrocyte proliferation. In vivo overexpression of NOTCH2NLB in the developing mouse cortex shifted progenitor output toward the astrocyte lineage, increasing the astrocyte-to-neuron ratio from the early postnatal period through adulthood. This phenotype was associated with an expansion of proliferative glial progenitors around birth. Single-nucleus transcriptomic profiling further showed that NOTCH2NLB suppresses neuronal gene programs while activating transcriptional modules related to cell proliferation and cellular homeostasis during gliogenesis. Together, these findings indicate that human-specific NOTCH2NL acts at a conserved developmental decision point to amplify astrocyte production. Our study extends the function of NOTCH2NL beyond neurogenesis and suggests that human lineage-specific gene duplications can modulate gliogenesis, providing a developmental mechanism that may have contributed to the coordinated expansion of neuronal and glial populations in the human cortex.

developmental biology↗

bioRxiv2025

Orthogonal Modes of Gene Expression Evolution Shape Human Neocortical Development and Disease Vulnerability

The neocortex is responsible for higher-order cognitive abilities such as language, abstract reasoning, and executive function--capacities that are particularly advanced in humans. To elucidate the molecular foundations of neocortical evolution in the human lineage, it is essential to examine how conserved gene repertoires have undergone expression changes relative to other mammals. The expression changes in conserved genes are widely regarded as key drivers of the phenotypic evolution of human-specific traits. In this study, we performed a comprehensive comparative single-cell transcriptomic analysis of fetal neocortical development across four mammalian species: human, macaque, mouse, and ferret. To validate human-specific expression changes, we further analyzed brain organoids derived from both human and chimpanzee stem cells. Genes exhibiting human-specific expression shifts were systematically classified along three orthogonal dimensions: overall expression level (Human Level Distinctive; HLD), temporal expression trend (Human Trend Distinctive; HTD), and differentiation lineage specificity (Human Differentiation trajectory Distinctive; HDD). HLD genes were frequently enriched for long introns and located near Human Accelerated Regions (HARs), and showed pronounced upregulation in humans. These genes were strongly associated with neurodevelopmental disorders such as autism spectrum disorder and developmental delay, as well as with megalencephaly and glioblastoma. HTD genes, in contrast, exhibited a unique pattern in humans, peaking early in development and subsequently declining--opposite to the steadily increasing trends observed in other species. These genes were significantly enriched for oxidative phosphorylation and ribosomal functions, pointing to a temporally restricted elevation in biosynthetic activity in early human corticogenesis. HDD genes displayed a marked shift in lineage-specific expression: cilia-related genes that are typically expressed in apical progenitors in non-human species were instead highly expressed in outer radial glia (oRGs) in humans. This spatial reorganization of ciliary gene activity suggests an oRG-specific adaptation in signaling architecture. Together, these results highlight the diversity of regulatory changes that have shaped human cortical development. Distinct classes of gene expression evolution--mediated in part by HARs--appear to have contributed not only to the expansion and increased complexity of the human neocortex, but also to its heightened vulnerability to neurodevelopmental and oncogenic pathologies. The identified human distinctive genes will be the target of future experimental verification to elucidate the precise molecular mechanisms regulating human-specific aspects of cortical development.

bioinformatics↗