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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.
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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
AIM: The aim of this study was to evaluate the diagnostic, therapeutic and evolutionary aspects of female inguinal hernia (ovarian hernia). PATIENTS AND METHODS: This was a prospective and descriptive study lasting 6 years (1st January 2014 to 31st December 2019). It included all girls aged 0 to 15 years old with ovarian hernia, received in the pediatric surgery department of the Hôpital National AmirouBoubacar Diallo in Niamey. The variables studied were the socio-demographic characteristics of the patients, personal and family history, and those related to diagnostic, therapeutic and evolutionary aspects. RESULTS: With 23 recorded cases, ovarian hernia had a hospital frequency of 8.7%. The average age of the patients was 5.6 years (range: 4 months and 11 years). The average duration of evolution before diagnosis was 8 months (range: 0 days and 36 months). The hernia was mainly located on the right side: 14 cases (60.85%). The hernial sac during the operation was most often empty: 11 cases (47.85%). It contained at least the ovary for 10 patients (43.5%). There were 2 cases of strangulated hernia (8.6%). All the patients benefited from a herniotomy. The average operating time was 26.7 days (range: 0 days and 146 days). No deaths and no postoperative complications were recorded after a 3-month follow-up. CONCLUSION: Ovarian hernia in this study is a rare condition often encountered in young girls. In spite of a late treatment, the therapeutic results were satisfactory.
BUT: Le but de cette étude était d'évaluer les aspects diagnostiques, thérapeutiques et évolutifs de la hernie inguinale de la fille (hernie de l'ovaire). PATIENTS ET MÉTHODES: Il s'agissait d'une étude prospective et descriptive portant sur une période de 6 ans (1er janvier 2014 au 31 décembre 2019). Elle incluait toutes les filles âgées de 0 à 15 ans présentant une hernie de l'ovaire reçus dans le service de chirurgie pédiatrique de l'Hôpital National Amirou Boubacar Diallo de Niamey. Les variables étudiées étaient les caractéristiques sociodémographiques des patientes, les antécédents personnels et familiaux et celles liées aux aspects diagnostiques, thérapeutiques et évolutifs. RÉSULTATS: Avec 23 cas recensés, la hernie de l'ovaire avait une fréquence hospitalière de 8,7%. Les patientes étaient en moyenne âgé de 5,6 ans (extrêmes : 4 mois et 11 ans). La durée moyenne d'évolution avant le diagnostic était de 8 mois (extrêmes : 0 jours et 36 mois). La hernie était principalement située à droite : 14 cas (60,85%). Le sac herniaire au cours de l'intervention était le plus souvent vide : 11 cas (47,85%). Il contenait au moins l'ovaire chez 10 patientes (43,5%). Il y avait 2 cas de hernie étranglée (8,6%). Toutes les patientes bénéficièrent d'une herniotomie. Le délai opératoire moyen était de 26,7 jours (extrêmes : 0 jours et 146 jours). Aucun décès et aucune complication postopératoire après un suivi de 3 mois n'avaient été enregistrés. CONCLUSION: La hernie de l'ovaire est dans cette étude une affection rare rencontrée souvent chez la petite fille. Malgré une prise en charge tardive les résultats thérapeutiques étaient satisfaisants.
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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
Accurate perception of guidance cues is crucial for cell and axon migration. During initial navigation in the spinal cord, commissural axons are kept insensitive to midline repellents. Upon midline crossing in the floor plate, they switch on responsiveness to Slit and Semaphorin repulsive signals and are thus propelled away and prevented from crossing back. Whether and how the different midline repellents control specific aspects of this navigation remain to be elucidated. We set up a paradigm for live-imaging and super-resolution analysis of PlexinA1, Neuropilin-2, and Robo1/2 receptor dynamics during commissural growth cone navigation in chick and mouse embryos. We uncovered a remarkable program of sensitization to midline cues achieved by unique spatiotemporal sequences of receptor allocation at the growth-cone surface that orchestrates receptor-specific growth-cone behavior changes. This reveals post-translational mechanisms whereby coincident guidance signals are temporally resolved to allow the generation of specific guidance responses.
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Axones/fisiología , Proteínas del Tejido Nervioso/metabolismo , Semaforinas/metabolismo , Animales , Membrana Celular/metabolismo , Embrión de Pollo , Pollos , Embrión de Mamíferos/metabolismo , Conos de Crecimiento/metabolismo , Ratones , Proteínas del Tejido Nervioso/química , Dominios Proteicos , Receptores de Superficie Celular/química , Receptores de Superficie Celular/metabolismo , Receptores Inmunológicos/metabolismo , Proteínas Recombinantes/metabolismo , Factores de Tiempo , Proteínas RoundaboutRESUMEN
Septins, discovered almost half a century ago in yeast, have prominent contributions in a broad range of morphological and functional processes from yeast to human. Septins now emerge as key players of neurodevelopment and more specifically of the mechanisms driving the complex morphological differentiation and compartmentalization of neurons that are fundamental to their function. We review here recent advances in Septin-mediated processes of neuron differentiation, which enlighten similarities and differences between neuron and yeast polarity programs.
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Saccharomyces cerevisiae , Diferenciación Celular , Humanos , Neurogénesis , Neuronas , SeptinasRESUMEN
Transmission of polarity established early during cell lineage history is emerging as a key process guiding cell differentiation. Highly polarized neurons provide a fascinating model to study inheritance of polarity over cell generations and across morphological transitions. Neural crest cells (NCCs) migrate to the dorsal root ganglia to generate neurons directly or after cell divisions in situ. Using live imaging of vertebrate embryo slices, we found that bipolar NCC progenitors lose their polarity, retracting their processes to round for division, but generate neurons with bipolar morphology by emitting processes from the same locations as the progenitor. Monitoring the dynamics of Septins, which play key roles in yeast polarity, indicates that Septin 7 tags process sites for re-initiation of process growth following mitosis. Interfering with Septins blocks this mechanism. Thus, Septins store polarity features during mitotic rounding so that daughters can reconstitute the initial progenitor polarity.