Xenotransplanted Human Cortical Neurons Reveal Species-Specific Development and Functional Integration into Mouse Visual Circuits

Linaro, Daniele; Vermaercke, Ben; Iwata, Ryohei; Ramaswamy, Arjun; Libé-Philippot, Baptiste; Boubakar, Leïla; Davis, Brittany A.; Wierda, Keimpe; Davie, Kristofer; Poovathingal, Suresh; Penttila, Pier-Andree; Bilheu, Angéline; Bruyne, Lore De; Gall, David; Conzelmann, Karl‐Klaus; Bonin, Vincent; Vanderhaeghen, Pierre

doi:10.1016/j.neuron.2019.10.002

Cited by 153 publications

(122 citation statements)

References 91 publications

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“…These observations indicate that hiPSC-derived neurons have a relatively prolonged development compared to dissociated rat neurons, consistent with the protracted development of the human brain (Dotti, Sullivan, and Banker 1988;Petanjek et al 2011). This further supports the emerging evidence showing species-dependent differences in developmental timing of human and non-human neurons in vivo and in vitro (Shi, Kirwan, and Livesey 2012;Espuny-Camacho et al 2013;Nicholas et al 2013;Otani et al 2016;Linaro et al 2019). We further analyzed the structural AIS organization in axons of hiPSC-derived neurons by quantifying the average fluorescence intensity profiles of Trim46 and AnkG (FIG 1F,G).…”

Section: Characterization Of Developmental Stages In Human Ipsc-derivsupporting

confidence: 84%

Quantitative mapping of transcriptome and proteome dynamics during polarization of human iPSC-derived neurons

Lindhout

Kooistra

Portegies

et al. 2020

Preprint

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Early neuronal development is a well-coordinated process in which neuronal stem cells differentiate into polarized neurons. This process has been well studied in classical non-human model systems, but to what extent this is recapitulated in human neurons remains unclear. To study neuronal polarization in human neurons, we cultured human iPSC-derived neurons, characterized early developmental stages, measured electrophysiological responses, and systematically profiled transcriptomic and proteomic dynamics during these steps. We found extensive remodeling of the neuron transcriptome and proteome, with altered mRNA expression of ~1,100 genes and different expression profiles of ~1,500 proteins during neuronal differentiation and polarization. We also identified a distinct stage in axon development marked by an increase in microtubule remodeling and apparent relocation of the axon initial segment from the distal to proximal axon. Our comprehensive characterization and quantitative map of transcriptome and proteome dynamics provides a solid framework for studying polarization in human neurons.(FOM, #16NEPH05, CJW). AUTHOR CONTRIBUTIONSFWL, RK and SP designed the research, conducted experiments, and wrote the article together with LJH. RS conducted and analyzed the mass spectrometry experiments supervised by MA, LJH performed and interpreted the electrophysiology data supervised by CJW, RK and BLS provided and interpreted the RNA sequencing analysis. HDM edited the article. CCH designed the experimental plan, supervised the research and wrote the article.

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Section: Characterization Of Developmental Stages In Human Ipsc-derivsupporting

confidence: 84%

Quantitative mapping of transcriptome and proteome dynamics during polarization of human iPSC-derived neurons

Lindhout

Kooistra

Portegies

et al. 2020

Preprint

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“…The delayed development and maturation of human neurons may have several possible consequences for the organization and function in the adult brain. The later onset of neurite outgrowth shown here and by others ( Otani et al, 2016 ; Marchetto et al, 2019 ; Petanjek et al, 2011 ; Linaro et al, 2019 ) has been speculated to result in more complex dendritic trees ( Bianchi et al, 2013a ; Elston et al, 2001 ; Marchetto et al, 2019 ). Interestingly, at d35, we find that the axons of the human multipolar neurons are slightly longer than in the ape neurons.…”

Section: Discussionsupporting

confidence: 70%

“…Recently, human iPSC-derived pyramidal neurons have been found to mature slower than their chimpanzee counterparts both structurally and functionally and to end up having higher dendrite complexity and spine density ( Marchetto et al, 2019 ). In addition, upon transplantation into the mouse neocortex human neurons were shown to retain juvenile-like dendritic spines dynamics and to mature both structurally and functionally over a protracted window of time ( Linaro et al, 2019 ). These findings are in line with previous studies suggesting that the human brain develops and matures slower than that of closely related primates ( Rakic, 2009 ; Somel et al, 2009 ; Charrier et al, 2012 ; Teffer et al, 2013 ) and point to the idea that human neurons and human brain develop with different temporal dynamics.…”

Section: Introductionmentioning

confidence: 99%

Comparison of induced neurons reveals slower structural and functional maturation in humans than in apes

Schörnig

Fast

et al. 2021

eLife

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We generated induced excitatory neurons (iNeurons, iNs) from chimpanzee, bonobo and human stem cells by expressing the transcription factor neurogenin‑2 (NGN2). Single cell RNA sequencing (scRNAseq) showed that genes involved in dendrite and synapse development are expressed earlier during iNs maturation in the chimpanzee and bonobo than the human cells. In accordance, during the first two weeks of differentiation, chimpanzee and bonobo iNs showed repetitive action potentials and more spontaneous excitatory activity than human iNs, and extended neurites of higher total length. However, the axons of human iNs were slightly longer at 5 weeks of differentiation. The timing of the establishment of neuronal polarity did not differ between the species. Chimpanzee, bonobo and human neurites eventually reached the same level of structural complexity. Thus, human iNs develop slower than chimpanzee and bonobo iNs and this difference in timing likely depends on functions downstream of NGN2.

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“…Having identified a global scaling factor for the GRN, we set out to investigate the mechanism that sets the timescale. We reasoned that the mechanism was likely to be cell-autonomous since the temporal differences are observed between mouse and human cells grown in the same conditions in vitro, and it has been shown that in vitro differentiated cells transplanted in a host follow their own species-specific dynamics ( 29–31 ). Since the directed differentiation towards MNs occurs in response to Shh signalling, we hypothesized that the delay in the GRN in human compared to mouse could be a consequence of a reduced response to signalling.…”

Section: Resultsmentioning

confidence: 99%

Species-specific developmental timing is associated with global differences in protein stability in mouse and human

Rayón

Stamataki

Pérez-Carrasco

et al. 2019

Preprint

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11What determines the pace of embryonic development? Although many molecular mechanisms controlling 12 developmental processes are evolutionarily conserved, the speed at which these operate can vary substantially 13 between species. For example, the same genetic programme, comprising sequential changes in transcriptional 14 states, governs the differentiation of motor neurons in mouse and human, but the tempo at which it operates differs 15 between species. Using in vitro directed differentiation of embryonic stem cells to motor neurons, we show that the 16 programme runs twice as fast in mouse as in human. We provide evidence that this is neither due to differences in 17 signalling, nor the genomic sequence of genes or their regulatory elements. Instead, we find an approximately two-18 fold increase in protein stability and cell cycle duration in human cells compared to mouse. This can account for the 19 slower pace of human development, indicating that global differences in key kinetic parameters play a major role in 20 interspecies differences in developmental tempo. 22 24Although the order and underlying molecular mechanisms are often indistinguishable between different species, the 25 pace at which they progress can differ substantially. For example, compared to their rodent counterparts, neural 26 progenitors in the primate cortex progress more slowly through a temporal sequence of neuronal subtype 27 production (3). Moreover, in different species of primates, the duration of progenitor expansion differs, which at 28 least partly accounts for differences in brain size (4, 5). Even in more evolutionary conserved regions of the central 29 nervous system (CNS) there are differences in tempo. The specification of neuronal subtype identity in the vertebrate 30 spinal cord involves a conserved and well-defined gene regulatory programme comprising a series of changes in 31 transcriptional state as cells acquire specific identities and differentiate from neural progenitors to post-mitotic 32 neurons (6). The pace of this process differs between species, despite the similarity in the regulatory programme 33 and the structural and functional correspondence of the resulting spinal cords. For example, the differentiation of 34 motor neurons (MNs), a prominent neuronal subtype of the spinal cord, takes less than a day in zebrafish, 3-4 days 35 in mouse, but in humans it takes ~2 weeks (7, 8). Moreover, differences in developmental tempo are not confined 36 to the CNS. The oscillatory gene expression that regulates the sequential formation of vertebrate body segments -37 the segmentation clock -has a period that ranges from ~30mins in zebrafish, to 2-3h in mouse, and 5-6h in human 38 (9)(10)(11). What causes this developmental allochrony -interspecies differences in developmental tempo -is unclear. 39To address this question, we set out to compare the generation of mouse and human MNs in the developing spinal 40 cord. Progenitors of the spinal cord arise from the caudal lateral epiblast in the posterior of the elongating...

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Xenotransplanted Human Cortical Neurons Reveal Species-Specific Development and Functional Integration into Mouse Visual Circuits

Cited by 153 publications

References 91 publications

Quantitative mapping of transcriptome and proteome dynamics during polarization of human iPSC-derived neurons

Quantitative mapping of transcriptome and proteome dynamics during polarization of human iPSC-derived neurons

Comparison of induced neurons reveals slower structural and functional maturation in humans than in apes

Species-specific developmental timing is associated with global differences in protein stability in mouse and human

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