The human-specific gene FRMPD2B couples postnatal experience to the expansion of cortical connectivity
Authors: E. Christopoulou, J. Zamith, P. Bonadonna, M. Rivero Romano, M. Vaudin, W. Nguyen, C. Brunet, C. Blugeon, S. Lemoine, F. Giudicelli, A. Baffet, C. Charrier
Abstract
The human neocortex is characterized by its uniquely prolonged postnatal developmental period during which experience sculpts neuronal circuits, a process essential to human cognitive abilities. Yet whether human-specific genetic innovations have shaped the activity-dependent mechanisms regulating circuit assembly remains unknown. Here, we identify the human-specific gene FRMPD2B as an activity- and experience-regulated modifier of cortical connectivity. FRMPD2B is primarily expressed in cortico-cortical projection neurons postnatally and throughout childhood. It promotes dendritic, axonal and synaptic development, and is required for proper morphogenesis in xenotransplanted human cortical neurons. FRMPD2B expression is bidirectionally regulated by neuronal activity and experience. This activity-responsiveness was gained after FRMPD2B arose through partial gene duplication, when a retrotransposon insertion remodeled its promoter. Our findings highlight how a series of genetic innovations have led to the emergence of a human-specific activity-regulated developmental program through which postnatal experience drives cortical connectivity expansion, linking genome evolution to human brain plasticity.
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A human-specific modifier of cortical connectivity and circuit functionEwoud R. E. Schmidt, Han-Zhi T. Zhao, Jung M. Park et al. · 2021 · Nature · cited 79 times · Not summarized yet
A human-specific SRGAP2C duplication is tested for effects on synapse density and cortical circuit function, linking human genetic innovations to cortical connectivity.
Abstract
The cognitive abilities that characterize humans are thought to emerge from unique features of the cortical circuit architecture of the human brain, which include increased cortico–cortical connectivity. However, the evolutionary origin of these changes in connectivity and how they affected cortical circuit function and behaviour are currently unknown. The human-specific gene duplication SRGAP2C emerged in the ancestral genome of the Homo lineage before the major phase of increase in brain size1,2. SRGAP2C expression in mice increases the density of excitatory and inhibitory synapses received by layer 2/3 pyramidal neurons (PNs)3–5. Here we show that the increased number of excitatory synaps…
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Synaptic neoteny of human cortical neurons requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibitionBaptiste Libé-Philippot, R. Iwata, Aleksandra J. Recupero et al. · 2024 · Neuron · cited 21 times · Not summarized yet
SRGAP2B/C knockdown in xenotransplanted human cortical neurons reveals effects on synaptic development and neoteny, another human-specific influence on cortical maturation.
Abstract
Summary Human-specific (HS) genes have been implicated in brain evolution, but their impact on human neuron development and diseases remains unclear. Here, we study SRGAP2B/C, two HS gene duplications of the ancestral synaptic gene SRGAP2A, in human cortical pyramidal neurons (CPNs) xenotransplanted in the mouse cortex. Downregulation of SRGAP2B/C in human CPNs led to strongly accelerated synaptic development, indicating their requirement for the neoteny that distinguishes human synaptogenesis. SRGAP2B/C genes promoted neoteny by reducing the synaptic levels of SRGAP2A,thereby increasing the postsynaptic accumulation of the SYNGAP1 protein, encoded by a major intellectual disability/autism s…
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Human-Specific NOTCH2NL Genes Expand Cortical Neurogenesis through Delta/Notch RegulationIkuo K. Suzuki, D. Gacquer, R. Van Heurck et al. · 2018 · Cell · cited 426 times · Not summarized yet
NOTCH2NL paralogs promote cortical progenitor maintenance and neurogenesis, addressing human-specific genetic contributions to cortical development rather than postnatal circuit connectivity.
Abstract
Summary The cerebral cortex underwent rapid expansion and increased complexity during recent hominid evolution. Gene duplications constitute a major evolutionary force, but their impact on human brain development remains unclear. Using tailored RNA sequencing (RNA-seq), we profiled the spatial and temporal expression of hominid-specific duplicated (HS) genes in the human fetal cortex and identified a repertoire of 35 HS genes displaying robust and dynamic patterns during cortical neurogenesis. Among them NOTCH2NL, human-specific paralogs of the NOTCH2 receptor, stood out for their ability to promote cortical progenitor maintenance. NOTCH2NL promote the clonal expansion of human cortical prog…
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Networks of Cultured iPSC-Derived Neurons Reveal the Human Synaptic Activity-Regulated Adaptive Gene ProgramP. Pruunsild, C. Bengtson, H. Bading · 2017 · Cell Reports · cited 74 times · Not summarized yet
Human iPSC-derived neuronal networks are used to identify activity-induced gene programs and species-specific responses, including genes absent or differently regulated in mice.
Abstract
Summary Long-term adaptive responses in the brain, such as learning and memory, require synaptic activity-regulated gene expression, which has been thoroughly investigated in rodents. Using human iPSC-derived neuronal networks, we show that the human and the mouse synaptic activity-induced transcriptional programs share many genes and both require Ca2+-regulated synapse-to-nucleus signaling. Species-specific differences include the noncoding RNA genes BRE-AS1 and LINC00473 and the protein-coding gene ZNF331, which are absent in the mouse genome, as well as several human genes whose orthologs are either not induced by activity or are induced with different kinetics in mice. These results indi…
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Human-specific morphoregulatory signatures in basal radial glia characterise neocortex evolutionTheresa M. Schütze, Annika Kolodziejczyk, Nora Ditzer et al. · 2025 · bioRxiv · cited 1 time · Not summarized yet
Comparative organoid profiling identifies human-specific regulatory elements in basal radial glia, focusing on progenitor biology rather than postnatal neuronal connectivity.
Abstract
As the seat of our cognition, the human neocortex is an object of immense fascination. Human neocortex expansion during evolution has been attributed to an increase in the proliferative capacity of neural progenitor cells during development, particularly basal radial glia (bRG). Despite their evolutionary relevance, the genomic changes driving human-specific bRG biology remain uncharacterized. We used comparative chromatin and transcriptional profiling of neural progenitor cells isolated from gorilla, chimpanzee and human cerebral organoids to identify cis-regulatory elements that have gained activity in humans. Focusing specifically on bRG, we discovered that morphoregulatory enhancer activ…
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Developmental rewiring of EHMT1 function during human cortical neurogenesisK. Kasliwal, K. Chatterjee, V. Bocchi et al. · 2026 · bioRxiv · preprint, not peer reviewed · Not summarized yet
EHMT1 is studied as a developmentally repurposed chromatin regulator during human cortical neurogenesis, rather than as an activity-regulated connectivity modifier.
Abstract
Ubiquitously expressed chromatin regulators orchestrate cell-type-specific gene expression programs, yet how they acquire distinct regulatory functions during development remains fundamentally unresolved1,2. Using temporally controlled protein depletion during human cortical neurogenesis in vitro, we show that the autism-associated histone methyltransferase EHMT13,4 is developmentally repurposed from epiblast to cortical neurons. Broadly expressed zinc finger proteins recruit EHMT1 to distinct cis-regulatory elements within changing chromatin landscapes associated with lineage-specific transcription factor activity, with extensive remodeling of EHMT1 enhancer occupancy during neural inductio…
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Molecular mechanisms of the specialization of human synapses in the neocortex.Eirini Christopoulou, Cécile Charrier · 2024 · Current Opinion in Genetics and Development · cited 4 times · Not summarized yet
This review surveys human-specific genetic and cellular mechanisms that specialize neocortical synapses and their extended development.
Abstract
Synapses of the neocortex specialized during human evolution to develop over extended timescales, process vast amounts of information and increase connectivity, which is thought to underlie our advanced social and cognitive abilities. These features reflect species-specific regulations of neuron and synapse cell biology. However, despite growing understanding of the human genome and the brain transcriptome at the single-cell level, linking human-specific genetic changes to the specialization of human synapses has remained experimentally challenging. In this review, we describe recent progress in characterizing divergent morphofunctional and developmental properties of human synapses, and we …
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Developmental mechanisms underlying the evolution of human cortical circuitsP. Vanderhaeghen, F. Polleux · 2023 · Nature Reviews Neuroscience · cited 155 times · Not summarized yet
This review covers human-specific modifiers across cortical development, including neurogenesis, synaptogenesis, and circuit assembly.
Abstract
The brain of modern humans has evolved remarkable computational abilities that enable higher cognitive functions. These capacities are tightly linked to an increase in the size and connectivity of the cerebral cortex, which is thought to have resulted from evolutionary changes in the mechanisms of cortical development. Convergent progress in evolutionary genomics, developmental biology and neuroscience has recently enabled the identification of genomic changes that act as human-specific modifiers of cortical development. These modifiers influence most aspects of corticogenesis, from the timing and complexity of cortical neurogenesis to synaptogenesis and the assembly of cortical circuits. Mu…
Prior work it builds on
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Extension of cortical synaptic development distinguishes humans from chimpanzees and macaques.Xi-Ling Liu, M. Somel, Lin Tang et al. · 2012 · Genome Research · cited 245 times · Not summarized yet
This study compares the duration of cortical synaptic development across humans, chimpanzees, and macaques, providing an evolutionary context for prolonged human plasticity.
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Human-specific gene ARHGAP11B promotes basal progenitor amplification and neocortex expansionMarta Florio, Mareike Albert, E. Taverna et al. · 2015 · Science · cited 628 times · Not summarized yet
ARHGAP11B is examined for its role in basal progenitor amplification and neocortex expansion, an earlier developmental aspect of human brain evolution.
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Visual deprivation and genetic analysis show how postnatal experience specifies cortical cell types, examining experience-dependent circuit development in mouse visual cortex.
Abstract
SUMMARY The role of postnatal experience in sculpting cortical circuitry, while long appreciated, is poorly understood at the level of cell types. We explore this in the mouse primary visual cortex (V1) using single-nucleus RNA-sequencing, visual deprivation, genetics, and functional imaging. We find that vision selectively drives the specification of glutamatergic cell types in upper layers (L) (L2/3/4), while deeper-layer glutamatergic, GABAergic, and non-neuronal cell types are established prior to eye opening. L2/3 cell types form an experience-dependent spatial continuum defined by the graded expression of ~200 genes, including regulators of cell adhesion and synapse formation. One of t…
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Experience-Dependent Structural Plasticity in the Visual SystemKalen Berry, E. Nedivi · 2016 · Annual Review of Vision Science · cited 52 times · Not summarized yet
This review surveys experience-dependent structural changes in visual circuits, including how synaptic rearrangements support adaptation and behavior.
Abstract
During development, the environment exerts a profound influence on the wiring of brain circuits. Due to the limited resolution of studies in fixed tissue, this experience-dependent structural plasticity was once thought to be restricted to a specific developmental time window. The recent introduction of two-photon microscopy for in vivo imaging has opened the door to repeated monitoring of individual neurons and the study of structural plasticity mechanisms at a very fine scale. In this review, we focus on recent work showing that synaptic structural rearrangements are a key mechanism mediating neural circuit adaptation and behavioral plasticity in the adult brain. We examine this work in th…
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Experience-dependent structural plasticity of pyramidal neurons in the developing sensory cortices.Miao Wang, Xiang Yu · 2023 · Current Opinion in Neurobiology · cited 7 times · Not summarized yet
This review summarizes how sensory experience alters pyramidal-neuron structure in developing and adult sensory cortices.
Abstract
Sensory experience regulates the structural and functional wiring of neuronal circuits, during development and throughout adulthood. Here, we review current knowledge of how experience affects structural plasticity of pyramidal neurons in the sensory cortices. We discuss the pros and cons of existing labeling approaches, as well as what structural parameters are most plastic. We further discuss how recent advances in sparse labeling of specific neuronal subtypes, as well as development of techniques that allow fast, high resolution imaging in large fields, would enable future studies to address currently unanswered questions in the field of structural plasticity.
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