Mitochondria metabolism sets the species-specific tempo of neuronal development

Iwata, Ryohei; Casimir, Pierre; Erkol, Emir; Boubakar, Leïla; Planque, Mélanie; López, Isabel M Gallego; Ditkowska, Martyna; Gaspariunaite, Vaiva; Beckers, Sofie; Remans, Daan; Vints, Katlijn; Vandekeere, Anke; Poovathingal, Suresh; Bird, Matthew; Corthout, Nikky; Vermeersch, Pieter; Carpentier, Sébastien; Davie, Kristofer; Mazzone, Massimiliano; Gounko, Natalia V.; Aerts, Stein; Ghesquière, Bart; Fendt, Sarah-Maria; Vanderhaeghen, Pierre

doi:10.1126/science.abn4705

Cited by 142 publications

(102 citation statements)

References 55 publications

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“…Across ExN clusters, isoforms of ENC1, ANKRD18CP, and RASD1 are enriched in ExN1, EnX2 and ExN3 cells, respectively (fig S10E-F). Moreover, vRG-ExN cells are defined by a majority of transcripts involved in mitochondrial metabolism, consistent with recent reports of the role of mitochondria in regulating neuronal maturation (75). Overall, the increased resolution in ExN and ExM cells obtained from isoform-based clustering matches the observed increase in isoform diversification in those cells (Fig.…”

Section: Novel Cell-types Uncovered From Isoform-level Clusteringsupporting

confidence: 90%

Developmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms

Patowary

Zhang

Jops

et al. 2023

Preprint

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Human brain development is under tight molecular genetic control and the recent advent of single-cell genomics has revolutionized our ability to elucidate the diverse underlying cell-types and states. Although RNA splicing is highly prevalent in the brain and has strong links to neuropsychiatric disorders, previous work has not systematically investigated the role of cell-type-specific splicing or transcript-isoform diversity during human brain development. Here, we leverage single molecule long-read sequencing to deeply profile the full-length transcriptome of the germinal zone (GZ) and cortical plate (CP) regions of the developing human neocortex at tissue and single-cell resolution. We identify 214,516 unique isoforms, corresponding to 22,391 genes. Remarkably, we find that 72.6% of these are novel and together with >7,000 novel-spliced exons expands the proteome by 92,422 proteoforms. We uncover myriad novel isoform switches during cortical neurogenesis, implicating previously-uncharacterized RNA-binding protein-mediated and other regulatory mechanisms in cellular identity and disease. Early-stage excitatory neurons exhibit the greatest isoform diversity and isoform-based single-cell clustering identifies previously uncharacterized cell states. Leveraging this resource, we re-prioritize thousands of rare de novo risk variants associated with neurodevelopmental disorders (NDDs) and reveal that risk genes are strongly associated with the number of unique isoforms observed per gene. Altogether, this work uncovers a substantial contribution of transcript-isoform diversity in cellular identity in the developing neocortex, elucidates novel genetic risk mechanisms for neurodevelopmental and neuropsychiatric disorders, and provides a comprehensive isoform-centric gene annotation for the developing human brain.

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Section: Novel Cell-types Uncovered From Isoform-level Clusteringsupporting

confidence: 90%

Developmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms

Patowary

Zhang

Jops

et al. 2023

Preprint

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“…Human cortical projection neurons (CPNs) develop at their species-specific tempo when xenotransplanted in the fast-developing mouse cortex, pointing to cell-intrinsic mechanisms ( 9–13 ). While mitochondria metabolism was recently shown to regulate the species-specific tempo of global neuronal maturation ( 14 ), one outstanding molecular candidate for the specific timing of synaptic maturation is the SRGAP2 gene family ( 15 ). This family is composed of SRGAP2A, the ancestral gene shared by all mammals, and human-specific (HS) gene duplicates SRGAP2B, SRGAP2C and SRGAP2D, which emerged through segmental duplications during recent hominin evolution ( 16, 17 ).…”

Section: Main Textmentioning

confidence: 99%

Human synaptic neoteny requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition

Libé-Philippot

Iwata

Recupero

et al. 2023

Preprint

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Human-specific (HS) genes are potential drivers of brain evolution, but their impact on human neuron development and disease remains unclear. Here we studied HS genes SRGAP2B/C in human cortical projection neurons (CPNs) in vivo, using xenotransplantation in the mouse cortex. Downregulation of SRGAP2B/C in human CPNs greatly accelerated synaptic development, indicating their requirement for human-specific synaptic neoteny. SRGAP2B/C acted by downregulating their ancestral paralog SRGAP2A, thereby upregulating postsynaptic levels of SYNGAP1, a major intellectual deficiency/autism spectrum disorder (ID/ASD) gene. Combinatorial genetic invalidation revealed that the tempo of synaptogenesis is set by a balance between SRGAP2A and SYNGAP1, which in human CPNs is tipped towards neoteny by SRGAP2B/C. Our results demonstrate that HS genes can modify the phenotypic expression of ID/ASD mutations through regulation of synaptic neoteny.One-Sentence SummaryHuman-specific genes SRGAP2B/C control human cortical neuron neoteny by regulating the function of neurodevelopmental disorder gene SYNGAP1

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“…It is widely recognized that properly functioning mitochondria are integral to normal brain development [ 6 , [19] , [20] , [21] ]. A new study has shown that different pace of neuronal development among species is attributable to differences in mitochondrial metabolism, especially oxidative phosphorylation [ 22 ]. Our findings provide a clearer view of mitochondrial respiration capacity in the developing brain.…”

Section: Discussionmentioning

confidence: 99%