Abstract
The delayed and prolonged postmitotic maturation of human neurons, compared with neurons from other species, may contribute to human-specific cognitive abilities and neurological disorders. Here we review the mechanisms of neuronal maturation, applying lessons from model systems to understand the specific features of protracted human cortical maturation and species differences. We cover cell-intrinsic features of neuronal maturation, including transcriptional, epigenetic and metabolic mechanisms, as well as cell-extrinsic features, including the roles of activity and synapses, the actions of glial cells and the contribution of the extracellular matrix. We discuss evidence for species differences in biochemical reaction rates, the proposed existence of an epigenetic maturation clock and the contributions of both general and modular mechanisms to species-specific maturation timing. Finally, we suggest approaches to measure, improve and accelerate the maturation of human neurons in culture, examine crosstalk and interactions among these different aspects of maturation and propose conceptual models to guide future studies.
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Anderson, V., Spencer-Smith, M. & Wood, A. Do children really recover better? Neurobehavioural plasticity after early brain insult. Brain 134, 2197–2221 (2011).
Duker, A., Jackson, A. & Bober, M. B. in GeneReviews (eds. Adam, M. P. et al.) https://www.ncbi.nlm.nih.gov/books/NBK575926/ (Univ. Washington, 2021).
Lui, J. H., Hansen, D. V. & Kriegstein, A. R. Development and evolution of the human neocortex. Cell 146, 18–36 (2011).
Miller, D. J., Bhaduri, A., Sestan, N. & Kriegstein, A. Shared and derived features of cellular diversity in the human cerebral cortex. Curr. Opin. Neurobiol. 56, 117–124 (2019).
Espinós, A., Fernández-Ortuño, E., Negri, E. & Borrell, V. Evolution of genetic mechanisms regulating cortical neurogenesis. Dev. Neurobiol. 82, 428–453 (2022).
Vaid, S. & Huttner, W. B. Progenitor-based cell biological aspects of neocortex development and evolution. Front. Cell Dev. Biol. 10, 892922 (2022).
Libé-Philippot, B. & Vanderhaeghen, P. Cellular and molecular mechanisms linking human cortical development and evolution. Annu. Rev. Genet. 55, 555–581 (2021).
Koo, B., Lee, K. H., Ming, G. L., Yoon, K. J. & Song, H. Setting the clock of neural progenitor cells during mammalian corticogenesis. Semin. Cell Dev. Biol. 142, 43–53 (2022).
Kuzawa, C. W. et al. Metabolic costs and evolutionary implications of human brain development. Proc. Natl Acad. Sci. USA 111, 13010–13015 (2014).
Gould, S. J. Ontogeny and Phylogeny (Harvard Univ. Press, 1977).
Otis, E. M. & Brent, R. Equivalent ages in mouse and human embryos. Anat. Rec. 120, 33–63 (1954).
Van den Ameele, J., Tiberi, L., Vanderhaeghen, P. & Espuny-Camacho, I. Thinking out of the dish: what to learn about cortical development using pluripotent stem cells. Trends Neurosci. 37, 334–342 (2014).
Ueda, S. et al. Sequence of molecular events during the maturation of the developing mouse prefrontal cortex. Mol. Neuropsychiatry 1, 94–104 (2015).
Miller, D. J. et al. Prolonged myelination in human neocortical evolution. Proc. Natl Acad. Sci. USA 109, 16480–16485 (2012). Quantification of myelination across human and chimpanzee development reveals dramatically delayed and prolonged myelination in humans from infancy to adulthood.
Petanjek, Z. et al. Extraordinary neoteny of synaptic spines in the human prefrontal cortex. Proc. Natl Acad. Sci. USA 108, 13281–13286 (2011).
Thompson, J. L. & Nelson, A. J. Middle childhood and modern human origins. Hum. Nat. 22, 249–280 (2011).
Davignon, R. W., Parker, R. M. & Hendrickx, A. G. Staging of the early embryonic brain in the baboon (Papio cynocephalus) and rhesus monkey (Macaca mulatta). Anat. Embryol. 159, 317–334 (1980).
O’Rahilly, R. & Müller, F. Developmental Stages in Human Embryos: Including a Revision of Streeter’s ‘Horizons’ and a Survey of the Carnegie Collection (Carnegie Institution of Washington, 1987).
Zhu, Y. et al. Spatiotemporal transcriptomic divergence across human and macaque brain development. Science 362, eaat8077 (2018). This RNA-seq atlas of primate brain development shows that divergence in gene expression between human and rhesus macaque is highest in the midfetal and adolescence periods and prominently involves synaptic and myelination genes.
Yuan, Y. et al. Development and application of a modified dynamic time warping algorithm (DTW-S) to analyses of primate brain expression time series. BMC Bioinform. 12, 347 (2011).
Khrameeva, E. et al. Single-cell-resolution transcriptome map of human, chimpanzee, bonobo, and macaque brains. Genome Res. 30, 776–789 (2020).
Herring, C. A. et al. Human prefrontal cortex gene regulatory dynamics from gestation to adulthood at single-cell resolution. Cell 185, 4428–4447.e28 (2022). Single-cell transcriptomics atlas that profiles the entire period of human cortical development, from gestation to adulthood, shows cell-type-specific maturation patterns.
Cheng, S. et al. Vision-dependent specification of cell types and function in the developing cortex. Cell 185, 311–327.e24 (2022). This mouse study provides a mechanistic example of the role of interactions between cell-extrinsic factors (vision-evoked activity) and cell-intrinsic factors (gene expression) in promoting cell-type-specific maturation.
Cossart, R. The maturation of cortical interneuron diversity: how multiple developmental journeys shape the emergence of proper network function. Curr. Opin. Neurobiol. 21, 160–168 (2011).
Nicholas, C. R. et al. Functional maturation of hPSC-derived forebrain interneurons requires an extended timeline and mimics human neural development. Cell Stem Cell 12, 573–586 (2013).
Maroof, A. M. et al. Directed differentiation and functional maturation of cortical interneurons from human embryonic stem cells. Cell Stem Cell 12, 559–572 (2013).
Hodge, R. D. et al. Conserved cell types with divergent features in human versus mouse cortex. Nature 573, 61–68 (2019).
Krienen, F. M. et al. Innovations present in the primate interneuron repertoire. Nature 586, 262–269 (2020).
Bakken, T. E. et al. Comparative cellular analysis of motor cortex in human, marmoset and mouse. Nature 598, 111–119 (2021).
Schmitz, M. T. et al. The development and evolution of inhibitory neurons in primate cerebrum. Nature 603, 871–877 (2022).
Suresh, H. et al. Comparative single-cell transcriptomic analysis of primate brains highlights human-specific regulatory evolution. Nat. Ecol. Evol. https://doi.org/10.1038/s41559-023-02186-7 (2023).
Beaulieu-Laroche, L. et al. Allometric rules for mammalian cortical layer 5 neuron biophysics. Nature 600, 274–278 (2021).
Campagnola, L. et al. Local connectivity and synaptic dynamics in mouse and human neocortex. Science 375, eabj5861 (2022).
Kalmbach, B. E. et al. Signature morpho-electric, transcriptomic, and dendritic properties of human layer 5 neocortical pyramidal neurons. Neuron 109, 2914–2927.e5 (2021).
Shi, Y., Kirwan, P., Smith, J., Robinson, H. P. C. & Livesey, F. J. Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses. Nat. Neurosci. 15, 477–486 (2012).
Barry, C. et al. Species-specific developmental timing is maintained by pluripotent stem cells ex utero. Dev. Biol. 423, 101–110 (2017).
Espuny-Camacho, I. et al. Pyramidal neurons derived from human pluripotent stem cells integrate efficiently into mouse brain circuits in vivo. Neuron 77, 440–456 (2013).
Linaro, D. et al. Xenotransplanted human cortical neurons reveal species-specific development and functional integration into mouse visual circuits. Neuron 104, 972–986 (2019). HPSC-CExNs transplanted into the mouse cortex exhibit slower development of morphological and electrophysiological properties than their mouse counterparts.
Marchetto, M. C. et al. Species-specific maturation profiles of human, chimpanzee and bonobo neural cells. eLife 8, e37527 (2019).
Bean, B. P. The action potential in mammalian central neurons. Nat. Rev. Neurosci. 8, 451–465 (2007).
Bardy, C. et al. Predicting the functional states of human iPSC-derived neurons with single-cell RNA-seq and electrophysiology. Mol. Psychiatry 21, 1573–1588 (2016).
Moore, A. R., Zhou, W.-L., Jakovcevski, I., Zecevic, N. & Antic, S. D. Spontaneous electrical activity in the human fetal cortex in vitro. J. Neurosci. 31, 2391–2398 (2011).
Tien, N.-W. & Kerschensteiner, D. Homeostatic plasticity in neural development. Neural Dev. 13, 9 (2018).
Bar-Shira, O., Maor, R. & Chechik, G. Gene expression switching of receptor subunits in human brain development. PLoS Comput. Biol. 11, e1004559 (2015).
Di Bella, D. J. et al. Molecular logic of cellular diversification in the mouse cerebral cortex. Nature 595, 554–559 (2021).
Somel, M. et al. Transcriptional neoteny in the human brain. Proc. Natl Acad. Sci. USA 106, 5743–5748 (2009). A comparative transcriptomics study that demonstrates delayed postnatal expression of neurodevelopmental genes in humans compared with chimpanzee and rhesus macaque.
Sousa, A. M. M. et al. Molecular and cellular reorganization of neural circuits in the human lineage. Science 358, 1027–1032 (2017).
Allaway, K. C. et al. Genetic and epigenetic coordination of cortical interneuron development. Nature 597, 693–697 (2021).
Azim, E., Shnider, S. J., Cederquist, G. Y., Shivraj Sohur, U. & Macklis, J. D. Lmo4 and Clim1 progressively delineate cortical projection neuron subtypes during development. Cereb. Cortex 19, 62–69 (2009).
Mayer, C. et al. Developmental diversification of cortical inhibitory interneurons. Nature 555, 457–462 (2018).
Klingler, E. et al. Temporal controls over inter-areal cortical projection neuron fate diversity. Nature 599, 453–457 (2021).
Poulopoulos, A. et al. Subcellular transcriptomes and proteomes of developing axon projections in the cerebral cortex. Nature 565, 356–360 (2019).
Liu, X. et al. Extension of cortical synaptic development distinguishes humans from chimpanzees and macaques. Genome Res. 22, 611–622 (2012).
Wang, L. et al. A cross-species proteomic map reveals neoteny of human synapse development. Nature 622, 112–119 (2023).
Ghosh, R. P. & Meyer, B. J. Spatial organization of chromatin: emergence of chromatin structure during development. Annu. Rev. Cell Dev. Biol. 37, 199–232 (2021).
Bonev, B. et al. Multiscale 3D genome rewiring during mouse neural development. Cell 171, 557–572.e24 (2017).
Closser, M. et al. An expansion of the non-coding genome and its regulatory potential underlies vertebrate neuronal diversity. Neuron 110, 70–85.e6 (2022).
Beagan, J. A. & Phillips-Cremins, J. E. On the existence and functionality of topologically associating domains. Nat. Genet. 52, 8–16 (2020).
Calderon, L. et al. Cohesin-dependence of neuronal gene expression relates to chromatin loop length. eLife 11, e76539 (2022).
Keough, K. C. et al. Three-dimensional genome rewiring in loci with human accelerated regions. Science 380, eabm1696 (2023).
Stergachis, A. B. et al. Developmental fate and cellular maturity encoded in human regulatory DNA landscapes. Cell 154, 888–903 (2013).
Hickey, S. L., Berto, S. & Konopka, G. Chromatin decondensation by FOXP2 promotes human neuron maturation and expression of neurodevelopmental disease genes. Cell Rep. 27, 1699–1711.e9 (2019).
Jones, P. L. et al. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat. Genet. 19, 187–191 (1998).
Horvath, S. & Raj, K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat. Rev. Genet. 19, 371–384 (2018).
Horvath, S. DNA methylation age of human tissues and cell types. Genome Biol. 14, R115 (2013).
Lister, R. et al. Global epigenomic reconfiguration during mammalian brain development. Science 341, 1237905 (2013).
Stroud, H. et al. Early-life gene expression in neurons modulates lasting epigenetic states. Cell 171, 1151–1164.e16 (2017).
Bintu, L. et al. Dynamics of epigenetic regulation at the single-cell level. Science 351, 720–724 (2016).
Pease, N. A. et al. Tunable, division-independent control of gene activation timing by a Polycomb switch. Cell Rep. 34, 108888 (2021). An epigenetic switch in T cells regulates the onset of gene activation via the competing actions of histone methyltransferase and demethylase activity to control H3K27me3 levels.
Chory, E. J. et al. Nucleosome turnover regulates histone methylation patterns over the genome. Mol. Cell 73, 61–72.e3 (2019).
Ciceri, G. et al. An epigenetic barrier sets the timing of human neuronal maturation. Preprint at bioRxiv https://doi.org/10.1101/2022.06.02.490114 (2022). Chemical inhibition or CRISPRi knockdown of key chromatin modifiers in either NPCs or postmitotic hPSC-CExNs can accelerate aspects of neuronal maturation.
Hergenreder, E. et al. Combined small molecule treatment accelerates timing of maturation in human pluripotent stem cell-derived neurons. Nat. Biotech. (in the press). Using a screening approach, the authors identify a set of factors, including inhibitors of chromatin modifiers and activators of calcium-dependent transcription, that accelerate maturation of hPSC-CExNs and other cell types.
Mätlik, K., Govek, E.-E., Paul, M. R., Allis, C. D. & Hatten, M. E. Histone bivalency regulates the timing of cerebellar granule cell development. Genes Dev. 37, 570–589 (2023).
Macrae, T. A., Fothergill-Robinson, J. & Ramalho-Santos, M. Regulation, functions and transmission of bivalent chromatin during mammalian development. Nat. Rev. Mol. Cell Biol. 24, 6–26 (2023).
Guo, J. U. et al. Neuronal activity modifies the DNA methylation landscape in the adult brain. Nat. Neurosci. 14, 1345–1351 (2011).
Su, Y. et al. Neuronal activity modifies the chromatin accessibility landscape in the adult brain. Nat. Neurosci. 20, 476–483 (2017).
Kitazawa, T. et al. A unique bipartite Polycomb signature regulates stimulus-response transcription during development. Nat. Genet. 53, 379–391 (2021).
Tang, Y., Liu, M.-L., Zang, T. & Zhang, C.-L. Direct reprogramming rather than iPSC-based reprogramming maintains aging hallmarks in human motor neurons. Front. Mol. Neurosci. 10, 359 (2017).
Cornacchia, D. & Studer, L. Back and forth in time: directing age in iPSC-derived lineages. Brain Res. 1656, 14–26 (2017).
Mertens, J. et al. Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients. Cell Stem Cell 28, 1533–1548.e6 (2021).
Miyazawa, H. & Aulehla, A. Revisiting the role of metabolism during development. Development 145, dev131110 (2018).
Zheng, X. et al. Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation. eLife 5, e13374 (2016). This mouse study documents the metabolic changes in glycolysis and OXPHOS pathways that occur during neuronal differentiation and maturation.
Knaus, L. S. et al. Large neutral amino acid levels tune perinatal neuronal excitability and survival. Cell 186, 1950–1967.e25 (2023). Perturbing an essential amino acid transporter involved in metabolic shifts in early postnatal development disrupts neuronal excitability and survival in mCExNs and provides a mechanistic explanation for a known genetic cause of human autism.
Iwata, R., Casimir, P. & Vanderhaeghen, P. Mitochondrial dynamics in postmitotic cells regulate neurogenesis. Science 369, 858–862 (2020).
Iwata, R. Temporal differences of neurodevelopment processes between species. Neurosci. Res. 177, 8–15 (2022).
Iwata, R. et al. Mitochondria metabolism sets the species-specific tempo of neuronal development. Science 379, eabn4705 (2023). A comparison of mouse and human neurons reveals prolonged mitochondrial development in hPSC-CExNs, and increasing mitochondrial tricarboxylic acid and OXPHOS pathways in hPSC-CExNs accelerates maturation.
Hock, M. B. & Kralli, A. Transcriptional control of mitochondrial biogenesis and function. Annu. Rev. Physiol. 71, 177–203 (2009).
Schvartzman, J. M., Thompson, C. B. & Finley, L. W. S. Metabolic regulation of chromatin modifications and gene expression. J. Cell Biol. 217, 2247–2259 (2018).
Dai, Z., Ramesh, V. & Locasale, J. W. The evolving metabolic landscape of chromatin biology and epigenetics. Nat. Rev. Genet. 21, 737–753 (2020).
Li, X., Egervari, G., Wang, Y., Berger, S. L. & Lu, Z. Regulation of chromatin and gene expression by metabolic enzymes and metabolites. Nat. Rev. Mol. Cell Biol. 19, 563–578 (2018).
Wrangham, R. W., Jones, J. H., Laden, G., Pilbeam, D. & Conklin-Brittain, N. The raw and the stolen. Cooking and the ecology of human origins. Curr. Anthropol. 40, 567–594 (1999).
Bhaduri, A. et al. Cell stress in cortical organoids impairs molecular subtype specification. Nature 578, 142–148 (2020).
Pollen, A. A. et al. Establishing cerebral organoids as models of human-specific brain evolution. Cell 176, 743–756.e17 (2019).
Faria-pereira, A., Temido-ferreira, M. & Morais, V. A. BrainPhys neuronal media support physiological function of mitochondria in mouse primary neuronal cultures. Front. Mol. Neurosci. 15, 837448 (2022).
Arjun McKinney, A., Petrova, R. & Panagiotakos, G. Calcium and activity-dependent signaling in the developing cerebral cortex. Development 149, dev198853 (2022). The authors review the functions of calcium signalling in early development and dysfunctions in neurodevelopmental disorders.
Hurni, N. et al. Transient cell-intrinsic activity regulates the migration and laminar positioning of cortical projection neurons. Cereb. Cortex 27, 3052–3063 (2017).
Bortone, D. & Polleux, F. KCC2 expression promotes the termination of cortical interneuron migration in a voltage-sensitive calcium-dependent manner. Neuron 62, 53–71 (2009).
Komuro, Y. et al. The role of calcium and cyclic nucleotide signaling in cerebellar granule cell migration under normal and pathological conditions. Dev. Neurobiol. 75, 369–387 (2015).
Rosenberg, S. S. & Spitzer, N. C. Calcium signaling in neuronal development. Cold Spring Harb. Perspect. Biol. 3, a004259 (2011).
Stroud, H. et al. An activity-mediated transition in transcription in early postnatal neurons. Neuron 107, 874–890.e8 (2020).
Yap, E. L. & Greenberg, M. E. Activity-regulated transcription: bridging the gap between neural activity and behavior. Neuron 100, 330–348 (2018).
Moore, A. R. et al. Electrical excitability of early neurons in the human cerebral cortex during the second trimester of gestation. Cereb. Cortex 19, 1795–1805 (2009).
Moore, A. R. et al. Connexin hemichannels contribute to spontaneous electrical activity in the human fetal cortex. Proc. Natl Acad. Sci. USA 111, E3919–E3928 (2014). Together with Moore et al. (2009) and Moore et al. (2011), this study is one of the first to characterize neuronal electrophysiology in the human fetal cortex, showing that subplate neurons mature first and early correlated activity is controlled by connexin hemichannels.
Peinado, A., Yuste, R. & Katz, L. C. Extensive dye coupling between rat neocortical neurons during the period of circuit formation. Neuron 10, 103–114 (1993).
Elias, L. A. B. & Kriegstein, A. R. Gap junctions: multifaceted regulators of embryonic cortical development. Trends Neurosci. 31, 243–250 (2008).
Munz, M. et al. Pyramidal neurons form active, transient, multilayered circuits perturbed by autism-associated mutations at the inception of neocortex. Cell 186, 1930–1949.e31 (2023).
Molnár, Z., Luhmann, H. J. & Kanold, P. O. Transient cortical circuits match spontaneous and sensory-driven activity during development. Science 370, eabb2153 (2020). The authors review the prenatal development of cortical electrophysiological properties and circuits with a focus on humans.
Ozair, M. Z. et al. hPSC modeling reveals that fate selection of cortical deep projection neurons occurs in the subplate. Cell Stem Cell 23, 60–73.e6 (2018).
Hoerder-Suabedissen, A. & Molnár, Z. Development, evolution and pathology of neocortical subplate neurons. Nat. Rev. Neurosci. 16, 133–146 (2015).
Moreno-Juan, V. et al. Prenatal thalamic waves regulate cortical area size prior to sensory processing. Nat. Commun. 8, 14172 (2017).
Li, H. et al. Laminar and columnar development of barrel cortex relies on thalamocortical neurotransmission. Neuron 79, 970–986 (2013).
Antón-bolaños, N. et al. Prenatal activity from thalamic neurons governs the emergence of functional cortical maps in mice. Science 990, 987–990 (2019).
Luhmann, H. J., Kanold, P. O., Molnár, Z. & Vanhatalo, S. Early brain activity: translations between bedside and laboratory. Prog. Neurobiol. 213, 102268 (2022).
Wong Fong Sang, I. E. et al. Optogenetically controlled activity pattern determines survival rate of developing neocortical neurons. Int. J. Mol. Sci. 22, 6575 (2021).
Wong, F. K. & Marín, O. Developmental cell death in the cerebral cortex. Annu. Rev. Cell Dev. Biol. 35, 523–542 (2019).
Rakic, S. & Zecevic, N. Programmed cell death in the developing human telencephalon. Eur. J. Neurosci. 12, 2721–2734 (2000).
Hensch, T. K. Critical period plasticity in local cortical circuits. Nat. Rev. Neurosci. 6, 877–888 (2005).
Ataman, B. et al. Evolution of osteocrin as an activity-regulated factor in the primate brain. Nature 539, 242–247 (2016).
Qian, X. et al. Sliced human cortical organoids for modeling distinct cortical layer formation. Cell Stem Cell 26, 766–781 (2020).
Karzbrun, E., Kshirsagar, A., Cohen, S. R., Hanna, J. H. & Reiner, O. Human brain organoids on a chip reveal the physics of folding. Nat. Phys. 14, 515–522 (2018).
Giandomenico, S. L., Sutcliffe, M. & Lancaster, M. A. Generation and long-term culture of advanced cerebral organoids for studying later stages of neural development. Nat. Protoc. 16, 579–602 (2020).
Sanes, J. R. & Zipursky, S. L. Synaptic specificity, recognition molecules, and assembly of neural circuits. Cell 181, 536–556 (2020).
Meijer, M. et al. A single-cell model for synaptic transmission and plasticity in human iPSC-derived neurons. Cell Rep. 27, 2199–2211.e6 (2019).
Trujillo, C. A. et al. Complex oscillatory waves emerging from cortical organoids model early human brain network development. Cell Stem Cell 25, 558–569.e7 (2019).
Sharf, T. et al. Functional neuronal circuitry and oscillatory dynamics in human brain organoids. Nat. Commun. 13, 4403 (2022).
Xiang, Y. et al. hESC-derived thalamic organoids form reciprocal projections when fused with cortical organoids. Cell Stem Cell 24, 487–497.e7 (2019).
Fligor, C. M. et al. Extension of retinofugal projections in an assembled model of human pluripotent stem cell-derived organoids. Stem Cell Rep. 16, 2228–2241 (2021).
Berto, S. et al. Accelerated evolution of oligodendrocytes in the human brain. Proc. Natl Acad. Sci. USA 116, 24334–24342 (2019).
Baldwin, K. T. & Eroglu, C. Molecular mechanisms of astrocyte-induced synaptogenesis. Curr. Opin. Neurobiol. 45, 113–120 (2017).
Banker, G. A. Trophic interactions between astroglial cells and hippocampal neurons in culture. Science 209, 809–810 (1980).
Ullian, E. M., Sapperstein, S. K., Christopherson, K. S. & Barres, B. A. Control of synapse number by glia. Science 291, 657–661 (2001).
Tang, X. et al. Astroglial cells regulate the developmental timeline of human neurons differentiated from induced pluripotent stem cells. Stem Cell Res. 11, 743–757 (2013).
Christopherson, K. S. et al. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120, 421–433 (2005).
Gan, K. J. & Südhof, T. C. Specific factors in blood from young but not old mice directly promote synapse formation and NMDA-receptor recruitment. Proc. Natl Acad. Sci. USA 116, 12524–12533 (2019).
Risher, W. C. et al. Astrocytes refine cortical connectivity at dendritic spines. eLife 3, e04047 (2014).
Stogsdill, J. A. et al. Astrocytic neuroligins control astrocyte morphogenesis and synaptogenesis. Nature 551, 192–197 (2017).
Irala, D. et al. Astrocyte-secreted neurocan controls inhibitory synapse formation and function. Preprint at bioRxiv https://doi.org/10.1101/2023.04.03.535448 (2023).
Carmona, M. A., Murai, K. K., Wang, L., Roberts, A. J. & Pasqualea, E. B. Glial ephrin-A3 regulates hippocampal dendritic spine morphology and glutamate transport. Proc. Natl Acad. Sci. USA 106, 12524–12529 (2009).
Hama, H., Hara, C., Yamaguchi, K. & Miyawaki, A. PKC signaling mediates global enhancement of excitatory synaptogenesis in neurons triggered by local contact with astrocytes. Neuron 41, 405–415 (2004).
Chung, W.-S. et al. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature 504, 394–400 (2013).
Oberheim, N. A. et al. Uniquely hominid features of adult human astrocytes. J. Neurosci. 29, 3276–3287 (2009).
Falcone, C. et al. Cortical interlaminar astrocytes across the therian mammal radiation. J. Comp. Neurol. 527, 1654–1674 (2019).
Falcone, C. et al. Redefining varicose projection astrocytes in primates. Glia 70, 145–154 (2022).
Allen, D. E. et al. Fate mapping of neural stem cell niches reveals distinct origins of human cortical astrocytes. Science 376, 1441–1446 (2022).
Lischka, F. W. et al. Neonatal mouse cortical but not isogenic human astrocyte feeder layers enhance the functional maturation of induced pluripotent stem cell-derived neurons in culture. Glia 66, 725–748 (2018).
Sloan, S. A. et al. Human astrocyte maturation captured in 3D cerebral cortical spheroids derived from pluripotent stem cells. Neuron 95, 779–790.e6 (2017).
Barbar, L. et al. CD49f is a novel marker of functional and reactive human iPSC-derived astrocytes. Neuron 107, 436–453.e12 (2020).
Hasel, P. et al. Neurons and neuronal activity control gene expression in astrocytes to regulate their development and metabolism. Nat. Commun. 8, 15132 (2017).
Berryer, M. H. et al. High-content synaptic phenotyping in human cellular models reveals a role for BET proteins in synapse assembly. eLife 12, e80168 (2023).
Padmashri, R. et al. Modeling human-specific interlaminar astrocytes in the mouse cerebral cortex. J. Comp. Neurol. 529, 802–810 (2021).
Han, X. et al. Forebrain engraftment by human glial progenitor cells enhances synaptic plasticity and learning in adult mice. Cell Stem Cell 12, 342–353 (2013).
Menassa, D. A. et al. The spatiotemporal dynamics of microglia across the human lifespan. Dev. Cell 57, 2127–2139.e6 (2022).
Tremblay, M.-È., Lowery, R. L. & Majewska, A. K. Microglial interactions with synapses are modulated by visual experience. PLoS Biol. 8, e1000527 (2010).
Wallace, J., Lord, J., Dissing-Olesen, L., Stevens, B. & Murthy, V. Microglial depletion disrupts normal functional development of adult-born neurons in the olfactory bulb. eLife 9, e50531 (2020).
Wake, H., Moorhouse, A. J., Jinno, S., Kohsaka, S. & Nabekura, J. Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J. Neurosci. 29, 3974–3980 (2009).
Eyo, U. & Molofsky, A. V. Defining microglial-synapse interactions. Science 381, 1155–1156 (2023).
Schafer, D. P., Lehrman, E. K. & Stevens, B. The ‘quad-partite’ synapse: microglia-synapse interactions in the developing and mature CNS. Glia 61, 24–36 (2013).
Stevens, B. et al. The classical complement cascade mediates CNS synapse elimination. Cell 131, 1164–1178 (2007).
Schafer, D. P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691–705 (2012).
Lehrman, E. K. et al. CD47 protects synapses from excess microglia-mediated pruning during development. Neuron 100, 120–134.e6 (2018).
Marin, I. A. et al. The nonclassical MHC class I Qa-1 expressed in layer 6 neurons regulates activity-dependent plasticity via microglial CD94/NKG2 in the cortex. Proc. Natl Acad. Sci. USA 119, e2203965119 (2022).
Stefansson, H. et al. Common variants conferring risk of schizophrenia. Nature 460, 744–747 (2009).
Sekar, A. et al. Schizophrenia risk from complex variation of complement component 4. Nature 530, 177–183 (2016).
The Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium. Genome-wide association study identifies five new schizophrenia loci. Nat. Genet. 43, 969–976 (2011).
Baum, M. L. et al. CUB and Sushi multiple domains 1 (CSMD1) opposes the complement cascade in neural tissues. Cold Spring Harb. Lab. https://doi.org/10.1101/2020.09.11.291427v1 (2020).
Hammond, T. R., Robinton, D. & Stevens, B. Microglia and the brain: complementary partners in development and disease. Annu. Rev. Cell Dev. Biol. 34, 523–544 (2018).
Weinhard, L. et al. Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction. Nat. Commun. 9, 1228 (2018).
Zhan, Y. et al. Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat. Neurosci. 17, 400–406 (2014).
Hoshiko, M., Arnoux, I., Avignone, E., Yamamoto, N. & Audinat, E. Deficiency of the microglial receptor CX3CR1 impairs postnatal functional development of thalamocortical synapses in the barrel cortex. J. Neurosci. 32, 15106–15111 (2012).
Nguyen, P. T. et al. Microglial remodeling of the extracellular matrix promotes synapse plasticity. Cell 182, 388–403.e15 (2020).
Popova, G. et al. Human microglia states are conserved across experimental models and regulate neural stem cell responses in chimeric organoids. Cell Stem Cell 28, 2153–2166.e6 (2021).
Sabate-Soler, S. et al. Microglia integration into human midbrain organoids leads to increased neuronal maturation and functionality. Glia 70, 1267–1288 (2022).
Marsh, S. E. et al. Dissection of artifactual and confounding glial signatures by single-cell sequencing of mouse and human brain. Nat. Neurosci. 25, 306–316 (2022).
Hammond, T. R. et al. Single-cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes. Immunity 50, 253–271.e6 (2019).
Li, Q. et al. Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing. Neuron 101, 207–223.e10 (2019).
Geirsdottir, L. et al. Cross-species single-cell analysis reveals divergence of the primate microglia program. Cell 179, 1609–1622.e16 (2019).
Huang, W. et al. Origins and proliferative states of human oligodendrocyte precursor cells. Cell 182, 594–608.e11 (2020).
Fletcher, J. L., Makowiecki, K., Cullen, C. L. & Young, K. M. Oligodendrogenesis and myelination regulate cortical development, plasticity and circuit function. Semin. Cell Dev. Biol. 118, 14–23 (2021).
Nishiyama, A., Shimizu, T., Sherafat, A. & Richardson, W. D. Life-long oligodendrocyte development and plasticity. Semin. Cell Dev. Biol. 116, 25–37 (2021).
Yakovlev, P. L. & Lecours, A. R. in Regional Development of the Brain in Early Life (ed. Minkowski, A.) 3–70 (Blackwell Science, 1967).
Bürgel, U. et al. White matter fiber tracts of the human brain: three-dimensional mapping at microscopic resolution, topography and intersubject variability. Neuroimage 29, 1092–1105 (2006).
Zonouzi, M. et al. Individual oligodendrocytes show bias for inhibitory axons in the neocortex. Cell Rep. 27, 2799–2808.e3 (2019).
Bonetto, G., Belin, D. & Káradóttir, R. T. Myelin: a gatekeeper of activity-dependent circuit plasticity? Science 374, eaba6905 (2021).
Scholz, J., Klein, M. C., Behrens, T. E. J. & Johansen-Berg, H. Training induces changes in white-matter architecture. Nat. Neurosci. 12, 1370–1371 (2009).
Wang, S. et al. Human iPSC-derived oligodendrocyte progenitor cells can myelinate and rescue a mouse model of congenital hypomyelination. Cell Stem Cell 12, 252–264 (2013).
García-León, J. A. et al. SOX10 single transcription factor-based fast and efficient generation of oligodendrocytes from human pluripotent stem cells. Stem Cell Rep. 10, 655–672 (2018).
Marton, R. M. et al. Differentiation and maturation of oligodendrocytes in human three-dimensional neural cultures. Nat. Neurosci. 22, 484–491 (2019).
Shaker, M. R. et al. Rapid and efficient generation of myelinating human oligodendrocytes in organoids. Front. Cell. Neurosci. 15, 631548 (2021).
Giamanco, K. A. & Matthews, R. T. Deconstructing the perineuronal net: cellular contributions and molecular composition of the neuronal extracellular matrix. Neuroscience 218, 367–384 (2012).
Geissler, M. et al. Primary hippocampal neurons, which lack four crucial extracellular matrix molecules, display abnormalities of synaptic structure and function and severe deficits in perineuronal net formation. J. Neurosci. 33, 7742–7755 (2013).
Omar, M. H. et al. CNS neurons deposit laminin α5 to stabilize synapses. Cell Rep. 21, 1281–1292 (2017).
Dityatev, A., Schachner, M. & Sonderegger, P. The dual role of the extracellular matrix in synaptic plasticity and homeostasis. Nat. Rev. Neurosci. 11, 735–746 (2010).
Genestine, M. et al. Vascular-derived SPARC and SerpinE1 regulate interneuron tangential migration and accelerate functional maturation of human stem cell-derived interneurons. eLife 10, e56063 (2021).
Long, K. R. & Huttner, W. B. How the extracellular matrix shapes neural development. Open Biol. 9, 180216 (2019).
Park, H. & Poo, M. M. Neurotrophin regulation of neural circuit development and function. Nat. Rev. Neurosci. 14, 7–23 (2013).
Ibáñez, C. F. & Andressoo, J.-O. Biology of GDNF and its receptors—relevance for disorders of the central nervous system. Neurobiol. Dis. 97, 80–89 (2017).
Long, K. R. & Huttner, W. B. The role of the extracellular matrix in neural progenitor cell proliferation and cortical folding during human neocortex development. Front. Cell. Neurosci. 15, 804649 (2021).
Sood, D. et al. Functional maturation of human neural stem cells in a 3D bioengineered brain model enriched with fetal brain-derived matrix. Sci. Rep. 9, 17874 (2019).
Song, I. & Dityatev, A. Crosstalk between glia, extracellular matrix and neurons. Brain Res. Bull. 136, 101–108 (2018).
Hyysalo, A. et al. Laminin α5 substrates promote survival, network formation and functional development of human pluripotent stem cell-derived neurons in vitro. Stem Cell Res. 24, 118–127 (2017).
Zhang, Z. N. et al. Layered hydrogels accelerate iPSC-derived neuronal maturation and reveal migration defects caused by MeCP2 dysfunction. Proc. Natl Acad. Sci. USA 113, 3185–3190 (2016).
Hartmann, J. et al. Alginate‐laminin hydrogel supports long‐term neuronal activity in 3D human induced pluripotent stem cell‐derived neuronal networks. Adv. Mater. Interfaces 10, 2200580 (2022).
Álvarez, Z. et al. Artificial extracellular matrix scaffolds of mobile molecules enhance maturation of human stem cell-derived neurons. Cell Stem Cell 30, 219–238.e14 (2023). Manipulating ECM physical properties in vitro accelerates neuronal maturation in hPSC-CExNs.
Goyal, M. S., Hawrylycz, M., Miller, J. A., Snyder, A. Z. & Raichle, M. E. Aerobic glycolysis in the human brain is associated with development and neotenous gene expression. Cell Metab. 19, 49–57 (2014).
Bogin, B. Evolutionary hypotheses for human childhood. Yearb. Phys. Anthropol. 40, 63–89 (1997).
Diaz-Cuadros, M. et al. In vitro characterization of the human segmentation clock. Nature 580, 113–118 (2020).
Matsuda, M. et al. Species-specific segmentation clock periods are due to differential biochemical reaction speeds. Science 369, 1450–1455 (2020). One of the first studies, to our knowledge, conducted in the PSM system to connect timing differences in human and mouse cells with biochemical reaction speeds, including transcription delays and protein turnover.
Rayon, T. et al. Species-specific pace of development is associated with differences in protein stability. Science 369, eaba7667 (2020). One of the first studies, to our knowledge, in spinal motor neurons to connect timing differences in human and mouse cells with biochemical reaction speeds, focusing on protein degradation rates.
Gillooly, J. F., Charnov, E. L., West, G. B., Savage, V. M. & Brown, J. H. Effects of size and temperature on developmental time. Nature 417, 70–73 (2002).
Heusner, A. A. Body size and energy metabolism. Annu. Rev. Nutr. 5, 267–293 (1985).
Diaz-Cuadros, M. et al. Metabolic regulation of species-specific developmental rates. Nature 613, 550–557 (2023). A higher mass-specific metabolic rate in mouse PSM cells is correlated with higher cytosolic NAD+ to NADH ratios, and manipulating this ratio in human PSM alters protein translation rates.
Lázaro, J. et al. A stem cell zoo uncovers intracellular scaling of developmental tempo across mammals. Cell Stem Cell 30, 938–949.e7 (2023). Stem cell models of PSM development across four mammalian species in addition to human and mouse show that biochemical reaction rates but not metabolic rates are correlated with developmental timing.
Nguyen, P., Pease, N. A. & Kueh, H. Y. Scalable control of developmental timetables by epigenetic switching networks. J. R. Soc. Interface 18, 20210109 (2021). A series of mathematical models describe how epigenetic regulators could control developmental timing and be modified by evolutionary changes.
Buontempo, S. et al. EZH2-mediated H3K27me3 targets transcriptional circuits of neuronal differentiation. Front. Neurosci. 16, 814144 (2022).
Ramesh, V., Liu, F., Minto, M. S., Chan, U. & West, A. E. Bidirectional regulation of postmitotic H3K27me3 distributions underlie cerebellar granule neuron maturation dynamics. eLife 12, e86273 (2023).
Pereira, J. D. et al. Ezh2, the histone methyltransferase of PRC2, regulates the balance between self-renewal and differentiation in the cerebral cortex. Proc. Natl Acad. Sci. USA 107, 15957–15962 (2010).
Telley, L. et al. Temporal patterning of apical progenitors and their daughter neurons in the developing neocortex. Science 364, eaav2522 (2019).
Wu, Q. et al. Selective translation of epigenetic modifiers affects the temporal pattern and differentiation of neural stem cells. Nat. Commun. 13, 470 (2022).
Charrier, C. et al. Inhibition of SRGAP2 function by its human-specific paralogs induces neoteny during spine maturation. Cell 149, 923–935 (2012). The human-specific duplicated gene SRGAP2C inhibits SRGAP2A activity, delaying dendritic spine maturation.
Dennis, M. Y. et al. Evolution of human-specific neural SRGAP2 genes by incomplete segmental duplication. Cell 149, 912–922 (2012).
Schmidt, E. R. E., Kupferman, J. V., Stackmann, M. & Polleux, F. The human-specific paralogs SRGAP2B and SRGAP2C differentially modulate SRGAP2A-dependent synaptic development. Sci. Rep. 9, 18692 (2019).
Fossati, M. et al. SRGAP2 and its human-specific paralog co-regulate the development of excitatory and inhibitory synapses. Neuron 91, 356–369 (2016).
Libe-Philippot, B. et al. Human synaptic neoteny requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition. Preprint at bioRxiv https://doi.org/10.1101/2023.03.01.530630 (2023).
Assendorp, N. et al. CTNND2 moderates neuronal excitation and links human evolution to prolonged synaptic development in the neocortex. Preprint at bioRxiv https://doi.org/10.1101/2022.09.13.507776 (2022).
Schmidt, E. R. E. et al. A human-specific modifier of cortical connectivity and circuit function. Nature 599, 640–644 (2021).
Linker, S. B. et al. Human-specific regulation of neural maturation identified by cross-primate transcriptomics. Curr. Biol. 32, 4797–4807.e5 (2022).
Jones, F. C. et al. The genomic basis of adaptive evolution in threespine sticklebacks. Nature 484, 55–61 (2012).
Hill, M. S., Vande Zande, P. & Wittkopp, P. J. Molecular and evolutionary processes generating variation in gene expression. Nat. Rev. Genet. 22, 203–215 (2021).
Chen, Y. et al. A versatile polypharmacology platform promotes cytoprotection and viability of human pluripotent and differentiated cells. Nat. Methods 18, 528–541 (2021).
Miller, J. D. et al. Human iPSC-based modeling of late-onset disease via progerin-induced aging. Cell Stem Cell 13, 691–705 (2013).
Walker, M. L. & Herndon, J. G. Menopause in nonhuman primates? Biol. Reprod. 79, 398–406 (2008).
Brust, V., Schindler, P. M. & Lewejohann, L. Lifetime development of behavioural phenotype in the house mouse (Mus musculus). Front. Zool. 12, S17 (2015).
Rakic, P. Timing of major ontogenetic events in the visual cortex of the rhesus monkey. UCLA Forum Med. Sci. 18, 3–40 (1975).
Silbereis, J. C., Pochareddy, S., Zhu, Y., Li, M. & Sestan, N. The cellular and molecular landscapes of the developing human central nervous system. Neuron 89, 248–268 (2015).
Schmechel, D. E. & Rakic, P. A Golgi study of radial glial cells in developing monkey telencephalon: morphogenesis and transformation into astrocytes. Anat. Embryol. 156, 115–152 (1979).
Ge, W.-P., Miyawaki, A., Gage, F. H., Jan, Y. N. & Jan, L. Y. Local generation of glia is a major astrocyte source in postnatal cortex. Nature 484, 376–380 (2012).
Sanai, N. et al. Corridors of migrating neurons in the human brain and their decline during infancy. Nature 478, 382–386 (2011).
Kim, J.-Y. & Paredes, M. F. Implications of extended inhibitory neuron development. Int. J. Mol. Sci. 22, 5113 (2021).
Huttenlocher, P. R. Synaptic density in human frontal cortex—developmental changes and effects of aging. Brain Res. 163, 195–205 (1979).
Bourgeois, J. P., Goldman-Rakic, P. S. & Rakic, P. Synaptogenesis in the prefrontal cortex of rhesus monkeys. Cereb. Cortex 4, 78–96 (1994).
Kroon, T., van Hugte, E., van Linge, L., Mansvelder, H. D. & Meredith, R. M. Early postnatal development of pyramidal neurons across layers of the mouse medial prefrontal cortex. Sci. Rep. 9, 5037 (2019).
Rakic, P., Bourgeois, J.-P. & Goldman-Rakic, P. S. in Progress in Brain Research (eds Van Pelt, J. et al.) 227–243 (Elsevier, 1994).
Shapiro, L. P., Parsons, R. G., Koleske, A. J. & Gourley, S. L. Differential expression of cytoskeletal regulatory factors in the adolescent prefrontal cortex: implications for cortical development. J. Neurosci. Res. 95, 1123–1143 (2017).
Duerksen, K., Barlow, W. E. & Stasior, O. G. Fused eyelids in premature infants. Ophthal. Plast. Reconstr. Surg. 10, 234–240 (1994).
West, S. & Williams, C. Amblyopia in children (aged 7 years or less). BMJ Clin. Evid. 2016, 0709 (2016).
Harwerth, R. S., Smith, E. L. III, Duncan, G. C., Crawford, M. L. & von Noorden, G. K. Multiple sensitive periods in the development of the primate visual system. Science 232, 235–238 (1986).
Reh, R. K. et al. Critical period regulation across multiple timescales. Proc. Natl Acad. Sci. USA 117, 23242–23251 (2020).
Larsen, B. & Luna, B. Adolescence as a neurobiological critical period for the development of higher-order cognition. Neurosci. Biobehav. Rev. 94, 179–195 (2018).
Pincus, M. et al. Chronic psychosocial stress and experimental pubertal delay affect socioemotional behavior and amygdala functional connectivity in adolescent female rhesus macaques. Psychoneuroendocrinology 127, 105154 (2021).
Pattwell, S. S. et al. Dynamic changes in neural circuitry during adolescence are associated with persistent attenuation of fear memories. Nat. Commun. 7, 11475 (2016).
Stevenson, N. J. et al. Functional maturation in preterm infants measured by serial recording of cortical activity. Sci. Rep. 7, 12969 (2017).
Zhou, Z. et al. Engineering longevity-design of a synthetic gene oscillator to slow cellular aging. Science 380, 376–381 (2023).
Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583–589 (2021).
Varadi, M. et al. AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models. Nucleic Acids Res. 50, D439–D444 (2021).
Eiraku, M. et al. Self-organized formation of polarized cortical tissues from ESCs and its active manipulation by extrinsic signals. Cell Stem Cell 3, 519–532 (2008).
Borghese, L. et al. Inhibition of notch signaling in human embryonic stem cell-derived neural stem cells delays G1/S phase transition and accelerates neuronal differentiation in vitro and in vivo. Stem Cell 28, 955–964 (2010).
Qi, Y. et al. Combined small-molecule inhibition accelerates the derivation of functional cortical neurons from human pluripotent stem cells. Nat. Biotechnol. 35, 154–163 (2017).
Kemp, P. J. et al. Improving and accelerating the differentiation and functional maturation of human stem cell-derived neurons: role of extracellular calcium and GABA. J. Physiol. 594, 6583–6594 (2016).
Bocchi, R., Masserdotti, G. & Götz, M. Direct neuronal reprogramming: fast forward from new concepts toward therapeutic approaches. Neuron 110, 366–393 (2022).
Zhang, Y. et al. Rapid single-step induction of functional neurons from human pluripotent stem cells. Neuron 78, 785–798 (2013).
Lin, H.-C. et al. NGN2 induces diverse neuron types from human pluripotency. Stem Cell Rep. 16, 2118–2127 (2021).
Nehme, R. et al. Combining NGN2 programming with developmental patterning generates human excitatory neurons with NMDAR-mediated synaptic transmission. Cell Rep. 23, 2509–2523 (2018).
Giandomenico, S. L. et al. Cerebral organoids at the air–liquid interface generate diverse nerve tracts with functional output. Nat. Neurosci. 22, 669–679 (2019).
Mansour, A. A. et al. An in vivo model of functional and vascularized human brain organoids. Nat. Biotechnol. 36, 432–441 (2018).
Revah, O. et al. Maturation and circuit integration of transplanted human cortical organoids. Nature 610, 319–326 (2022). More advanced maturation phenotypes are demonstrated in organoids transplanted in mice versus those maintained in vitro.
Brewer, G. J., Torricelli, J. R., Evege, E. K. & Price, P. J. Optimized survival of hippocampal neurons in B27‐supplemented neurobasalTM, a new serum‐free medium combination. J. Neurosci. Res. 35, 567–576 (1993).
Brewer, G. J. & Cotman, C. W. Survival and growth of hippocampal neurons in defined medium at low density: advantages of a sandwich culture technique or low oxygen. Brain Res. 494, 65–74 (1989).
Bardy, C. et al. Neuronal medium that supports basic synaptic functions and activity of human neurons in vitro. Proc. Natl Acad. Sci. USA 112, E3312 (2015).
Gordon, A. et al. Long-term maturation of human cortical organoids matches key early postnatal transitions. Nat. Neurosci. 24, 331–342 (2021).
Bledi, Y., Domb, A. J. & Linial, M. Culturing neuronal cells on surfaces coated by a novel polyethyleneimine-based polymer. Brain Res. Brain Res. Protoc. 5, 282–289 (2000).
Hyvärinen, T. et al. Functional characterization of human pluripotent stem cell-derived cortical networks differentiated on laminin-521 substrate: comparison to rat cortical cultures. Sci. Rep. 9, 17125 (2019).
Sozzi, E. et al. Silk scaffolding drives self-assembly of functional and mature human brain organoids. Front. Cell Dev. Biol. 10, 1023279 (2022).
Kaech, S. & Banker, G. Culturing hippocampal neurons. Nat. Protoc. 1, 2406–2415 (2006).
Cakir, B. et al. Engineering of human brain organoids with a functional vascular-like system. Nat. Methods 16, 1169–1175 (2019).
Pham, M. T. et al. Generation of human vascularized brain organoids. Neuroreport 29, 588–593 (2018).
Johnson, M. A., Weick, J. P., Pearce, R. A. & Zhang, S.-C. Functional neural development from human embryonic stem cells: accelerated synaptic activity via astrocyte coculture. J. Neurosci. 27, 3069–3077 (2007).
Gao, Y. et al. Multimodal analysis of neuronal maturation in the developing primate prefrontal cortex. Preprint at bioRxiv https://doi.org/10.1101/2023.06.02.543460 (2023).
Werner, J. M. & Gillis, J. Preservation of co-expression defines the primary tissue fidelity of human neural organoids. Preprint at bioRxiv https://doi.org/10.1101/2023.03.31.535112 (2023).
Romero, I. G., Ruvinsky, I. & Gilad, Y. Comparative studies of gene expression and the evolution of gene regulation. Nat. Rev. Genet. 13, 505–516 (2012).
Pollen, A. A., Kilik, U., Lowe, C. B. & Camp, J. G. Human-specific genetics: new tools to explore the molecular and cellular basis of human evolution. Nat. Rev. Genet. 24, 687–711 (2023).
Müller, J. et al. High-resolution CMOS MEA platform to study neurons at subcellular, cellular, and network levels. Lab. Chip 15, 2767–2780 (2015).
Acknowledgements
The authors acknowledge C. Chen, S. Nolbrant, B. Pavlovic and A. Sousa for helpful discussions and comments on the manuscript and funding from the following funding sources: Jane Coffin Childs (J.L.W.), Schmidt Science Fellows (J.L.W.), US National Institutes of Health DP2MH122400-01 (A.A.P.) and Schmidt Futures Foundation (A.A.P.). A.A.P. is a New York Stem Cell Foundation Robertson Investigator.
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Glossary
- Activity-regulated genes
-
Genes whose expression levels are regulated by levels or patterns of neuronal activity. These include a first wave of early response genes (also known as immediate early genes) and a second wave of late response genes.
- Bivalent promoters
-
Promoters whose surrounding histones bear both active H3K4me2/3 (di- or trimethylation of histone 3 lysine 4) and repressive H3K27me3 (trimethylation of histone 3 lysine 27) marks, thought to prepare the expression of genes that are turned on at later developmental timepoints.
- Cell-extrinsic factors
-
Factors that originate externally to a cell (components of the environment) and that influence the properties or responses of the cell.
- Cell-intrinsic factors
-
Factors that originate from within a cell and are preserved even when the cell is removed from its native environment.
- Chromatin
-
A complex found in the nucleus of a cell that comprises DNA and associated proteins that organize, package and regulate DNA replication and gene expression.
- cis-regulatory mechanisms
-
Mechanisms in which cis-regulatory elements control the expression of individual genes nearby on the chromosome.
- Cortical plate
-
Term for nascent cortical layers II–VI during embryonic development before the laminar cytoarchitecture becomes distinct.
- Enhancers
-
Genomic elements distal to gene promoters that regulate gene expression levels and/or probability; an example of cis-regulatory elements.
- Glycolysis
-
A metabolic pathway that takes place in the cytoplasm in which cells produce ATP and lactate/pyruvate, which may be processed further by oxidative phosphorylation. This pathway is less efficient for ATP production than oxidative phosphorylation.
- Heterochrony
-
Evolutionary changes in developmental timing.
- Histone modifications
-
Chemical alterations (including acetylation and methylation) of the amino acids in histone proteins, which regulate gene expression and chromatin compaction.
- Multimodal methods
-
Methods for cellular characterization that combine two or more methods from different categories (for example, molecular, structural, functional and metabolic).
- Neotenous
-
Exhibits retention of juvenile characteristics in a sexually mature adult.
- Neuronal maturation
-
The process by which postmitotic neurons undergo molecular, metabolic, morphological and functional changes; engage in cellular interactions (including the establishment of synaptic connectivity and myelination); and achieve a steady-state phenotype in the adult brain.
- Nucleosomes
-
Protein complexes that each contain eight histones, around which DNA is coiled.
- Oxidative phosphorylation
-
(OXPHOS). A metabolic pathway that takes place in mitochondria in which cells use products of glucose metabolism and oxygen to produce energy in the form of ATP.
- Subplate
-
A transient layer of neurons located between the proliferative zone and the cortical plate. The subplate mostly disappears before birth, owing to cell migration and apoptosis, and the remaining cells become layer VIb neurons.
- Topologically associating domains
-
(TADs). Units of genome organization in which there are higher levels of chromatin interaction internally than externally, demarcating boundaries of looping interactions between enhancers and promoters.
- Transcription factors
-
Proteins that bind to DNA at enhancers and/or promoters to regulate gene expression; an example of trans-regulation.
- trans-regulatory mechanisms
-
Mechanisms in which trans-regulatory factors coordinate the activity of large suites of genes.
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Wallace, J.L., Pollen, A.A. Human neuronal maturation comes of age: cellular mechanisms and species differences. Nat. Rev. Neurosci. 25, 7–29 (2024). https://doi.org/10.1038/s41583-023-00760-3
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