RESUMEN
Human brain ontogeny is characterized by a considerably prolonged neotenic development of cortical neurons and circuits. Neoteny is thought to be essential for the acquisition of advanced cognitive functions, which are typically altered in intellectual disability (ID) and autism spectrum disorders (ASDs). Human neuronal neoteny could be disrupted in some forms of ID and/or ASDs, but this has never been tested. Here, we use xenotransplantation of human cortical neurons into the mouse brain to model SYNGAP1 haploinsufficiency, one of the most prevalent genetic causes of ID/ASDs. We find that SYNGAP1-deficient human neurons display strong acceleration of morphological and functional synaptic formation and maturation alongside disrupted synaptic plasticity. At the circuit level, SYNGAP1-haploinsufficient neurons display precocious acquisition of responsiveness to visual stimulation months ahead of time. Our findings indicate that SYNGAP1 is required cell autonomously for human neuronal neoteny, providing novel links between human-specific developmental mechanisms and ID/ASDs.
RESUMEN
Development consists of a highly ordered suite of steps and transitions, like choreography. Although these sequences are often evolutionarily conserved, they can display species variations in duration and speed, thereby modifying final organ size or function. Despite their evolutionary significance, the mechanisms underlying species-specific scaling of developmental tempo have remained unclear. Here, we will review recent findings that implicate global cellular mechanisms, particularly intermediary and protein metabolism, as species-specific modifiers of developmental tempo. In various systems, from somitic cell oscillations to neuronal development, metabolic pathways display species differences. These have been linked to mitochondrial metabolism, which can influence the species-specific speed of developmental transitions. Thus, intermediary metabolic pathways regulate developmental tempo together with other global processes, including proteostasis and chromatin remodeling. By linking metabolism and the evolution of developmental trajectories, these findings provide opportunities to decipher how species-specific cellular timing can influence organism fitness.
Asunto(s)
Especificidad de la Especie , Animales , Humanos , Mitocondrias/metabolismo , Evolución Biológica , Redes y Vías Metabólicas , Regulación del Desarrollo de la Expresión GénicaRESUMEN
Changes in developmental timing are an important factor of evolution in organ shape and function. This is particularly striking for human brain development, which, compared with other mammals, is considerably prolonged at the level of the cerebral cortex, resulting in brain neoteny. Here, we review recent findings that indicate that mitochondria and metabolism contribute to species differences in the tempo of cortical neuron development. Mitochondria display species-specific developmental timeline and metabolic activity patterns that are highly correlated with the speed of neuron maturation. Enhancing mitochondrial activity in human cortical neurons results in their accelerated maturation, while its reduction leads to decreased maturation rates in mouse neurons. Together with other global and gene-specific mechanisms, mitochondria thus act as a cellular hourglass of neuronal developmental tempo and may thereby contribute to species-specific features of human brain ontogeny.
Asunto(s)
Evolución Biológica , Encéfalo , Mitocondrias , Neuronas , Humanos , Mitocondrias/metabolismo , Mitocondrias/genética , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Animales , Neuronas/metabolismo , Neuronas/citología , Especificidad de la Especie , Neurogénesis/genética , RatonesRESUMEN
Neuronal activity-dependent transcription plays a key role in plasticity and pathology in the brain. An intriguing question is how neuronal activity controls gene expression via interactions of transcription factors with DNA and chromatin modifiers in the nucleus. By utilizing single-molecule imaging in human embryonic stem cell (ESC)-derived cortical neurons, we demonstrate that neuronal activity increases repetitive emergence of cAMP response element-binding protein (CREB) at histone acetylation sites in the nucleus, where RNA polymerase II (RNAPII) accumulation and FOS expression occur rapidly. Neuronal activity also enhances co-localization of CREB and CREB-binding protein (CBP). Increased binding of a constitutively active CREB to CBP efficiently induces CREB repetitive emergence. On the other hand, the formation of histone acetylation sites is dependent on CBP histone modification via acetyltransferase (HAT) activity but is not affected by neuronal activity. Taken together, our results suggest that neuronal activity promotes repetitive CREB-CRE and CREB-CBP interactions at predetermined histone acetylation sites, leading to rapid gene expression.
Asunto(s)
Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Histonas , Humanos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Histonas/metabolismo , ADN/metabolismo , Proteína de Unión a CREB/genética , Proteína de Unión a CREB/metabolismo , Expresión Génica , Neuronas/metabolismo , Acetilación , Histona Acetiltransferasas/genética , Histona Acetiltransferasas/metabolismoRESUMEN
The enhanced cognitive abilities characterizing the human species result from specialized features of neurons and circuits. Here, we report that the hominid-specific gene LRRC37B encodes a receptor expressed in human cortical pyramidal neurons (CPNs) and selectively localized to the axon initial segment (AIS), the subcellular compartment triggering action potentials. Ectopic expression of LRRC37B in mouse CPNs in vivo leads to reduced intrinsic excitability, a distinctive feature of some classes of human CPNs. Molecularly, LRRC37B binds to the secreted ligand FGF13A and to the voltage-gated sodium channel (Nav) ß-subunit SCN1B. LRRC37B concentrates inhibitory effects of FGF13A on Nav channel function, thereby reducing excitability, specifically at the AIS level. Electrophysiological recordings in adult human cortical slices reveal lower neuronal excitability in human CPNs expressing LRRC37B. LRRC37B thus acts as a species-specific modifier of human neuron excitability, linking human genome and cell evolution, with important implications for human brain function and diseases.
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Neuronas , Células Piramidales , Canales de Sodio Activados por Voltaje , Animales , Humanos , Ratones , Potenciales de Acción/fisiología , Axones/metabolismo , Neuronas/metabolismo , Canales de Sodio Activados por Voltaje/genética , Canales de Sodio Activados por Voltaje/metabolismoRESUMEN
mRNA localization and local translation enable exquisite spatial and temporal control of gene expression, particularly in polarized, elongated cells. These features are especially prominent in radial glial cells (RGCs), which are neural and glial precursors of the developing cerebral cortex and scaffolds for migrating neurons. Yet the mechanisms by which subcellular RGC compartments accomplish their diverse functions are poorly understood. Here, we demonstrate that mRNA localization and local translation of the RhoGAP ARHGAP11A in the basal endfeet of RGCs control their morphology and mediate neuronal positioning. Arhgap11a transcript and protein exhibit conserved localization to RGC basal structures in mice and humans, conferred by the 5' UTR. Proper RGC morphology relies upon active Arhgap11a mRNA transport and localization to the basal endfeet, where ARHGAP11A is locally synthesized. This translation is essential for positioning interneurons at the basement membrane. Thus, local translation spatially and acutely activates Rho signaling in RGCs to compartmentalize neural progenitor functions.
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Células Ependimogliales , Neuroglía , Humanos , Ratones , Animales , Células Ependimogliales/metabolismo , ARN Mensajero/metabolismo , Neuroglía/metabolismo , Neurogénesis , Corteza Cerebral , Proteínas Activadoras de GTPasa/genética , Proteínas Activadoras de GTPasa/metabolismoRESUMEN
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. Mutations of human-specific genetic modifiers of corticogenesis have started to be linked to neurodevelopmental disorders, providing evidence for their physiological relevance and suggesting potential relationships between the evolution of the human brain and its sensitivity to specific diseases.
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Corteza Cerebral , Neurogénesis , Humanos , Corteza Cerebral/fisiología , EncéfaloRESUMEN
Neuronal development in the human cerebral cortex is considerably prolonged compared with that of other mammals. We explored whether mitochondria influence the species-specific timing of cortical neuron maturation. By comparing human and mouse cortical neuronal maturation at high temporal and cell resolution, we found a slower mitochondria development in human cortical neurons compared with that in the mouse, together with lower mitochondria metabolic activity, particularly that of oxidative phosphorylation. Stimulation of mitochondria metabolism in human neurons resulted in accelerated development in vitro and in vivo, leading to maturation of cells weeks ahead of time, whereas its inhibition in mouse neurons led to decreased rates of maturation. Mitochondria are thus important regulators of the pace of neuronal development underlying human-specific brain neoteny.
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Mitocondrias , Neurogénesis , Neuronas , Animales , Humanos , Ratones , Corteza Cerebral/citología , Corteza Cerebral/crecimiento & desarrollo , Metabolismo Energético , Mitocondrias/metabolismo , Neuronas/metabolismoRESUMEN
The primary cilium is a central signaling component during embryonic development. Here we focus on CROCCP2, a hominid-specific gene duplicate from ciliary rootlet coiled coil (CROCC), also known as rootletin, that encodes the major component of the ciliary rootlet. We find that CROCCP2 is highly expressed in the human fetal brain and not in other primate species. CROCCP2 gain of function in the mouse embryonic cortex and human cortical cells and organoids results in decreased ciliogenesis and increased cortical progenitor amplification, particularly basal progenitors. CROCCP2 decreases ciliary dynamics by inhibition of the IFT20 ciliary trafficking protein, which then impacts neurogenesis through increased mTOR signaling. Loss of function of CROCCP2 in human cortical cells and organoids leads to increased ciliogenesis, decreased mTOR signaling, and impaired basal progenitor amplification. These data identify CROCCP2 as a human-specific modifier of cortical neurogenesis that acts through modulation of ciliary dynamics and mTOR signaling.
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Cilios , Transducción de Señal , Animales , Humanos , Ratones , Cilios/metabolismo , Citoesqueleto/metabolismo , Neurogénesis , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Despite its importance to understanding human brain (dys)function, it has remained challenging to study human neurons in vivo. Recent approaches, using transplantation of human cortical neurons into the rodent brain, offer new prospects for the study of human neural function and disease in vivo, from molecular to circuit levels.
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Encéfalo , Neuronas , Humanos , Neuronas/fisiología , Encéfalo/fisiología , Células MadreRESUMEN
The cerebral cortex is at the core of brain functions that are thought to be particularly developed in the human species. Human cortex specificities stem from divergent features of corticogenesis, leading to increased cortical size and complexity. Underlying cellular mechanisms include prolonged patterns of neuronal generation and maturation, as well as the amplification of specific types of stem/progenitor cells. While the gene regulatory networks of corticogenesis appear to be largely conserved among all mammals including humans, they have evolved in primates, particularly in the human species, through the emergence of rapidly divergent transcriptional regulatory elements, as well as recently duplicated novel genes. These human-specific molecular features together control key cellular milestones of human corticogenesis and are often affected in neurodevelopmental disorders, thus linking human neural development, evolution, and diseases.
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Corteza Cerebral , Neurogénesis , Animales , Corteza Cerebral/fisiología , Redes Reguladoras de Genes/genética , Humanos , Mamíferos , Neurogénesis/genéticaRESUMEN
Neural stem cells (NSCs) undergo massive molecular and cellular changes during neuronal differentiation. These include mitochondria and metabolism remodelling, which were thought to be mostly permissive cues, but recent work indicates that they are causally linked to neurogenesis. Striking remodelling of mitochondria occurs right after mitosis of NSCs, which influences the postmitotic daughter cells towards self-renewal or differentiation. The transitioning to neuronal fate requires metabolic rewiring including increased oxidative phosphorylation activity, which drives transcriptional and epigenetic effects to influence cell fate. Mitochondria metabolic pathways also contribute in an essential way to the regulation of NSC proliferation and self-renewal. The influence of mitochondria and metabolism on neurogenesis is conserved from fly to human systems, but also displays striking differences linked to cell context or species. These new findings have important implications for our understanding of neurodevelopmental diseases and possibly human brain evolution.
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Células-Madre Neurales , Neurogénesis , Diferenciación Celular , Proliferación Celular , Humanos , Mitocondrias , Células-Madre Neurales/metabolismoRESUMEN
During embryonic development, neural stem/progenitor cells generate hundreds of different cell types through the combination of intrinsic and extrinsic cues. Recent data obtained in mouse and human cortical neurogenesis provide novel views about this interplay and how it evolves with time, whether during irreversible cell fate transitions that neural stem cells undergo to become neurons, or through gradual temporal changes of competence that lead to increased neuronal diversity from a common stem cell pool. In each case the temporal changes result from a dynamic balance between intracellular states and extracellular signalling factors. The underlying mechanisms are mostly conserved across species, but some display unique features in human corticogenesis, thereby linking temporal features of neurogenesis and human brain evolution.
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Células-Madre Neurales , Neuronas , Animales , Diferenciación Celular , Ratones , Neurogénesis , Transducción de SeñalRESUMEN
Neonatal diabetes is caused by single gene mutations reducing pancreatic ß cell number or impairing ß cell function. Understanding the genetic basis of rare diabetes subtypes highlights fundamental biological processes in ß cells. We identified 6 patients from 5 families with homozygous mutations in the YIPF5 gene, which is involved in trafficking between the endoplasmic reticulum (ER) and the Golgi. All patients had neonatal/early-onset diabetes, severe microcephaly, and epilepsy. YIPF5 is expressed during human brain development, in adult brain and pancreatic islets. We used 3 human ß cell models (YIPF5 silencing in EndoC-ßH1 cells, YIPF5 knockout and mutation knockin in embryonic stem cells, and patient-derived induced pluripotent stem cells) to investigate the mechanism through which YIPF5 loss of function affects ß cells. Loss of YIPF5 function in stem cell-derived islet cells resulted in proinsulin retention in the ER, marked ER stress, and ß cell failure. Partial YIPF5 silencing in EndoC-ßH1 cells and a patient mutation in stem cells increased the ß cell sensitivity to ER stress-induced apoptosis. We report recessive YIPF5 mutations as the genetic cause of a congenital syndrome of microcephaly, epilepsy, and neonatal/early-onset diabetes, highlighting a critical role of YIPF5 in ß cells and neurons. We believe this is the first report of mutations disrupting the ER-to-Golgi trafficking, resulting in diabetes.
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Diabetes Mellitus , Estrés del Retículo Endoplásmico/genética , Enfermedades Genéticas Congénitas , Enfermedades del Recién Nacido , Microcefalia , Mutación , Proteínas de Transporte Vesicular , Línea Celular , Diabetes Mellitus/embriología , Diabetes Mellitus/genética , Diabetes Mellitus/patología , Femenino , Enfermedades Genéticas Congénitas/embriología , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/patología , Células Madre Embrionarias Humanas/metabolismo , Células Madre Embrionarias Humanas/patología , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/patología , Recién Nacido , Enfermedades del Recién Nacido/embriología , Enfermedades del Recién Nacido/genética , Enfermedades del Recién Nacido/patología , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Masculino , Microcefalia/embriología , Microcefalia/genética , Microcefalia/patología , Neuronas/metabolismo , Neuronas/patología , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismoRESUMEN
The conversion of neural stem cells into neurons is associated with the remodeling of organelles, but whether and how this is causally linked to fate change is poorly understood. We examined and manipulated mitochondrial dynamics during mouse and human cortical neurogenesis. We reveal that shortly after cortical stem cells have divided, daughter cells destined to self-renew undergo mitochondrial fusion, whereas those that retain high levels of mitochondria fission become neurons. Increased mitochondria fission promotes neuronal fate, whereas induction of mitochondria fusion after mitosis redirects daughter cells toward self-renewal. This occurs during a restricted time window that is doubled in human cells, in line with their increased self-renewal capacity. Our data reveal a postmitotic period of fate plasticity in which mitochondrial dynamics are linked with cell fate.
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Corteza Cerebral/crecimiento & desarrollo , Mitocondrias/fisiología , Dinámicas Mitocondriales , Mitosis , Células-Madre Neurales/citología , Neurogénesis/fisiología , Neuronas/citología , Animales , Corteza Cerebral/citología , Femenino , Células HEK293 , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Masculino , Ratones , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Sirtuinas/metabolismoRESUMEN
How neural circuits develop in the human brain has remained almost impossible to study at the neuronal level. Here, we investigate human cortical neuron development, plasticity, and function using a mouse/human chimera model in which xenotransplanted human cortical pyramidal neurons integrate as single cells into the mouse cortex. Combined neuronal tracing, electrophysiology, and in vivo structural and functional imaging of the transplanted cells reveal a coordinated developmental roadmap recapitulating key milestones of human cortical neuron development. The human neurons display a prolonged developmental timeline, indicating the neuron-intrinsic retention of juvenile properties as an important component of human brain neoteny. Following maturation, human neurons in the visual cortex display tuned, decorrelated responses to visual stimuli, like mouse neurons, demonstrating their capacity for physiological synaptic integration in host cortical circuits. These findings provide new insights into human neuronal development and open novel avenues for the study of human neuronal function and disease. VIDEO ABSTRACT.
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Neurogénesis/fisiología , Células Piramidales/citología , Células Piramidales/fisiología , Células Piramidales/trasplante , Animales , Diferenciación Celular/fisiología , Xenoinjertos , Humanos , Ratones , Corteza Visual/citología , Corteza Visual/fisiologíaRESUMEN
During neurogenesis, progenitors switch from self-renewal to differentiation through the interplay of intrinsic and extrinsic cues, but how these are integrated remains poorly understood. Here, we combine whole-genome transcriptional and epigenetic analyses with in vivo functional studies to demonstrate that Bcl6, a transcriptional repressor previously reported to promote cortical neurogenesis, acts as a driver of the neurogenic transition through direct silencing of a selective repertoire of genes belonging to multiple extrinsic pathways promoting self-renewal, most strikingly the Wnt pathway. At the molecular level, Bcl6 represses its targets through Sirt1 recruitment followed by histone deacetylation. Our data identify a molecular logic by which a single cell-intrinsic factor represses multiple extrinsic pathways that favor self-renewal, thereby ensuring robustness of neuronal fate transition.
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Autorrenovación de las Células/genética , Represión Epigenética/genética , Histonas/metabolismo , Células-Madre Neurales/metabolismo , Neurogénesis/genética , Proteínas Proto-Oncogénicas c-bcl-6/genética , Sirtuina 1/metabolismo , Animales , Factores de Crecimiento de Fibroblastos/metabolismo , Perfilación de la Expresión Génica , Proteínas Hedgehog/metabolismo , Código de Histonas , Ratones , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , RNA-Seq , Receptores Notch/metabolismo , Transducción de Señal/genética , Vía de Señalización Wnt/genéticaRESUMEN
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 progenitors, ultimately leading to higher neuronal output. At the molecular level, NOTCH2NL function by activating the Notch pathway through inhibition of cis Delta/Notch interactions. Our study uncovers a large repertoire of recently evolved genes active during human corticogenesis and reveals how human-specific NOTCH paralogs may have contributed to the expansion of the human cortex.
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Corteza Cerebral/metabolismo , Regulación de la Expresión Génica , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteínas de la Membrana/metabolismo , Neurogénesis , Neuronas/metabolismo , Receptor Notch2/genética , Secuencia de Aminoácidos , Proteínas de Unión al Calcio , Diferenciación Celular/genética , Análisis por Conglomerados , Perfilación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Humanos , Hibridación in Situ , Células-Madre Neurales/metabolismo , Transducción de SeñalRESUMEN
The transplantation of pluripotent stem-cell-derived neurons constitutes a promising avenue for the treatment of several brain diseases. However, their potential for the repair of the cerebral cortex remains unclear, given its complexity and neuronal diversity. Here, we show that human visual cortical cells differentiated from embryonic stem cells can be transplanted and can integrate successfully into the lesioned mouse adult visual cortex. The transplanted human neurons expressed the appropriate repertoire of markers of six cortical layers, projected axons to specific visual cortical targets, and were synaptically active within the adult brain. Moreover, transplant maturation and integration were much less efficient following transplantation into the lesioned motor cortex, as previously observed for transplanted mouse cortical neurons. These data constitute an important milestone for the potential use of human PSC-derived cortical cells for the reassembly of cortical circuits and emphasize the importance of cortical areal identity for successful transplantation.