RESUMEN

The cell-intrinsic mechanisms underlying the decision of a stem/progenitor cell to either proliferate or differentiate remain incompletely understood. Here, we identify the transmembrane protein Lrig1 as a physiological homeostatic regulator of FGF2-driven proliferation and self-renewal of neural progenitors at early-to-mid embryonic stages of cortical development. We show that Lrig1 is expressed in cortical progenitors (CPs), and its ablation caused expansion and increased proliferation of radial/apical progenitors and of neurogenic transit-amplifying Tbr2+ intermediate progenitors. Notably, our findings identify a previously unreported EGF-independent mechanism through which Lrig1 negatively regulates neural progenitor proliferation by modulating the FGF2-induced IL6/Jak2/Stat3 pathway, a molecular cascade that plays a pivotal role in the generation and maintenance of CPs. Consistently, Lrig1 knockout mice showed a significant increase in the density of pyramidal glutamatergic neurons placed in superficial layers 2 and 3 of the postnatal neocortex. Together, these results support a model in which Lrig1 regulates cortical neurogenesis by influencing the cycling activity of a set of progenitors that are temporally specified to produce upper layer glutamatergic neurons.

Asunto(s)

Janus Quinasa 2 , Glicoproteínas de Membrana , Ratones Noqueados , Células-Madre Neurales , Neurogénesis , Neuronas , Factor de Transcripción STAT3 , Transducción de Señal , Animales , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Janus Quinasa 2/metabolismo , Células-Madre Neurales/metabolismo , Células-Madre Neurales/citología , Ratones , Neurogénesis/genética , Neuronas/metabolismo , Neuronas/citología , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Proliferación Celular , Corteza Cerebral/metabolismo , Corteza Cerebral/citología , Corteza Cerebral/embriología , Diferenciación Celular , Factores de Crecimiento de Fibroblastos/metabolismo , Proteínas del Tejido Nervioso

RESUMEN

The emergence of myelinating oligodendrocytes represents a pivotal developmental milestone in vertebrates, given their capacity to ensheath axons and facilitate the swift conduction of action potentials. It is widely accepted that cortical oligodendrocyte progenitor cells (OPCs) arise from medial ganglionic eminence (MGE), lateral/caudal ganglionic eminence (LGE/CGE), and cortical radial glial cells (RGCs). Here, we used two different fate mapping strategies to challenge the established notion that the LGE generates cortical OPCs. Furthermore, we used a Cre/loxP-dependent exclusion strategy to reveal that the LGE/CGE does not give rise to cortical OPCs. Additionally, we showed that specifically eliminating MGE-derived OPCs leads to a significant reduction of cortical OPCs. Together, our findings indicate that the LGE does not generate cortical OPCs, contrary to previous beliefs. These findings provide a new view of the developmental origins of cortical OPCs and a valuable foundation for future research on both normal development and oligodendrocyte-related disease.

Asunto(s)

Corteza Cerebral , Oligodendroglía , Animales , Oligodendroglía/fisiología , Oligodendroglía/citología , Ratones , Corteza Cerebral/embriología , Corteza Cerebral/fisiología , Corteza Cerebral/citología , Células Precursoras de Oligodendrocitos/fisiología , Células Precursoras de Oligodendrocitos/citología , Diferenciación Celular , Eminencia Ganglionar

RESUMEN

It is well known that the human cortex is expanded compared with other mammalian species, but the molecular mechanisms underpinning the evolution of human corticogenesis are not well understood. A new paper in Development takes a novel computational approach to screen for genetic changes that could have played an important role in human brain evolution. To learn more about the story behind the paper, we caught up with first author Juan Moriano and corresponding author Cedric Boeckx, a Research Professor at Catalan Institute for Research and Advanced Studies (ICREA).

Asunto(s)

Evolución Biológica , Humanos , Animales , Historia del Siglo XXI , Corteza Cerebral/embriología , Historia del Siglo XX , Encéfalo/embriología , Encéfalo/metabolismo

RESUMEN

ADP ribosylation factor-like GTPase 2 (Arl2) is crucial for controlling mitochondrial fusion and microtubule assembly in various organisms. Arl2 regulates the asymmetric division of neural stem cells in Drosophila via microtubule growth. However, the function of mammalian Arl2 during cortical development was unknown. Here, we demonstrate that mouse Arl2 plays a new role in corticogenesis via regulating microtubule growth, but not mitochondria functions. Arl2 knockdown (KD) leads to impaired proliferation of neural progenitor cells (NPCs) and neuronal migration. Arl2 KD in mouse NPCs significantly diminishes centrosomal microtubule growth and delocalization of centrosomal proteins Cdk5rap2 and γ-tubulin. Moreover, Arl2 physically associates with Cdk5rap2 by in silico prediction using AlphaFold multimer, which was validated by co-immunoprecipitation and proximity ligation assay. Remarkably, Cdk5rap2 overexpression significantly rescues the neurogenesis defects caused by Arl2 KD. Therefore, Arl2 plays an important role in mouse cortical development through microtubule growth via the centrosomal protein Cdk5rap2.

Asunto(s)

Proteínas de Ciclo Celular , Centrosoma , Microtúbulos , Proteínas del Tejido Nervioso , Células-Madre Neurales , Neurogénesis , Animales , Microtúbulos/metabolismo , Ratones , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Neurogénesis/genética , Células-Madre Neurales/metabolismo , Centrosoma/metabolismo , Proliferación Celular , Movimiento Celular , Corteza Cerebral/metabolismo , Corteza Cerebral/embriología , Corteza Cerebral/crecimiento & desarrollo , Tubulina (Proteína)/metabolismo , Proteínas de Unión al GTP/metabolismo , Proteínas de Unión al GTP/genética , Factores de Ribosilacion-ADP/metabolismo , Factores de Ribosilacion-ADP/genética

RESUMEN

Folding of the cerebral cortex is a key aspect of mammalian brain development and evolution, and defects are linked to severe neurological disorders. Primary folding occurs in highly stereotyped patterns that are predefined in the cortical germinal zones by a transcriptomic protomap. The gene regulatory landscape governing the emergence of this folding protomap remains unknown. We characterized the spatiotemporal dynamics of gene expression and active epigenetic landscape (H3K27ac) across prospective folds and fissures in ferret. Our results show that the transcriptomic protomap begins to emerge at early embryonic stages, and it involves cell-fate signaling pathways. The H3K27ac landscape reveals developmental cell-fate restriction and engages known developmental regulators, including the transcription factor Cux2. Manipulating Cux2 expression in cortical progenitors changed their proliferation and the folding pattern in ferret, caused by selective transcriptional changes as revealed by single-cell RNA sequencing analyses. Our findings highlight the key relevance of epigenetic mechanisms in defining the patterns of cerebral cortex folding.

Asunto(s)

Corteza Cerebral , Epigénesis Genética , Hurones , Regulación del Desarrollo de la Expresión Génica , Animales , Corteza Cerebral/metabolismo , Corteza Cerebral/embriología , Hurones/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transcriptoma , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Histonas/metabolismo , Histonas/genética , Redes Reguladoras de Genes

RESUMEN

During the second-to-third trimester, the neuronal pathways of the fetal brain experience rapid development, resulting in the complex architecture of the interwired network at birth. While diffusion MRI-based tractography has been employed to study the prenatal development of structural connectivity network (SCN) in preterm neonatal and postmortem fetal brains, the in utero development of SCN in the normal fetal brain remains largely unknown. In this study, we utilized in utero dMRI data from human fetuses of both sexes between 26 and 38 gestational weeks to investigate the developmental trajectories of the fetal brain SCN, focusing on intrahemispheric connections. Our analysis revealed significant increases in global efficiency, mean local efficiency, and clustering coefficient, along with significant decrease in shortest path length, while small-worldness persisted during the studied period, revealing balanced network integration and segregation. Widespread short-ranged connectivity strengthened significantly. The nodal strength developed in a posterior-to-anterior and medial-to-lateral order, reflecting a spatiotemporal gradient in cortical network connectivity development. Moreover, we observed distinct lateralization patterns in the fetal brain SCN. Globally, there was a leftward lateralization in network efficiency, clustering coefficient, and small-worldness. The regional lateralization patterns in most language, motor, and visual-related areas were consistent with prior knowledge, except for Wernicke's area, indicating lateralized brain wiring is an innate property of the human brain starting from the fetal period. Our findings provided a comprehensive view of the development of the fetal brain SCN and its lateralization, as a normative template that may be used to characterize atypical development.

Asunto(s)

Imagen de Difusión por Resonancia Magnética , Red Nerviosa , Tercer Trimestre del Embarazo , Humanos , Femenino , Masculino , Embarazo , Imagen de Difusión por Resonancia Magnética/métodos , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/embriología , Red Nerviosa/fisiología , Red Nerviosa/crecimiento & desarrollo , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/embriología , Segundo Trimestre del Embarazo , Vías Nerviosas/embriología , Vías Nerviosas/diagnóstico por imagen , Vías Nerviosas/fisiología , Feto/diagnóstico por imagen , Desarrollo Fetal/fisiología , Imagen de Difusión Tensora/métodos

RESUMEN

Proper topographically organized neural connections between the thalamus and the cerebral cortex are mandatory for thalamus function. Thalamocortical (TC) fiber growth begins during the embryonic period and completes by the third trimester of gestation, so that human neonates at birth have a thalamus with a near-facsimile of adult functional parcellation. Whether congenital neocortical anomaly (e.g., lissencephaly) affects TC connection in humans is unknown. Here, via diffusion MRI fiber-tractography analysis of long-term formalin-fixed postmortem fetal brain diagnosed as lissencephaly in comparison with an age-matched normal one, we found similar topological patterns of thalamic subregions and of internal capsule parcellated by TC fibers. However, lissencephaly fetal brain showed white matter structural changes, including fewer/less organized TC fibers and optic radiations, and much less cortical plate invasion by TC fibers - particularly around the shallow central sulcus. Diffusion MRI fiber tractography of normal fetal brains at 15, 23, and 26 gestational weeks (GW) revealed dynamic volumetric change of each parcellated thalamic subregion, suggesting coupled developmental progress of the thalamus with the corresponding cortex. Moreover, from GW23 and GW26 normal fetal brains, TC endings in the cortical plate could be delineated to reflect cumulative progressive TC invasion of cortical plate. By contrast, lissencephaly brain showed a dramatic decrease in TC invasion of the cortical plate. Our study thus shows the feasibility of diffusion MRI fiber tractography in postmortem long-term formalin-fixed fetal brains to disclose the developmental progress of TC tracts coordinating with thalamic and neocortical growth both in normal and lissencephaly fetal brains at mid-gestational stage.

Asunto(s)

Corteza Cerebral , Imagen de Difusión Tensora , Lisencefalia , Vías Nerviosas , Tálamo , Humanos , Tálamo/diagnóstico por imagen , Tálamo/patología , Tálamo/embriología , Corteza Cerebral/patología , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/embriología , Lisencefalia/patología , Lisencefalia/diagnóstico por imagen , Vías Nerviosas/patología , Vías Nerviosas/diagnóstico por imagen , Vías Nerviosas/embriología , Imagen de Difusión Tensora/métodos , Feto/patología , Feto/diagnóstico por imagen , Edad Gestacional , Femenino , Masculino , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Sustancia Blanca/embriología , Imagen de Difusión por Resonancia Magnética/métodos

RESUMEN

Nucleotide changes in gene regulatory elements are important determinants of neuronal development and diseases. Using massively parallel reporter assays in primary human cells from mid-gestation cortex and cerebral organoids, we interrogated the cis-regulatory activity of 102,767 open chromatin regions, including thousands of sequences with cell type-specific accessibility and variants associated with brain gene regulation. In primary cells, we identified 46,802 active enhancer sequences and 164 variants that alter enhancer activity. Activity was comparable in organoids and primary cells, suggesting that organoids provide an adequate model for the developing cortex. Using deep learning we decoded the sequence basis and upstream regulators of enhancer activity. This work establishes a comprehensive catalog of functional gene regulatory elements and variants in human neuronal development.

Asunto(s)

Corteza Cerebral , Neurogénesis , Organoides , Humanos , Corteza Cerebral/embriología , Corteza Cerebral/metabolismo , Cromatina/metabolismo , Cromatina/genética , Aprendizaje Profundo , Elementos de Facilitación Genéticos , Regulación del Desarrollo de la Expresión Génica , Neurogénesis/genética , Neuronas/metabolismo , Organoides/metabolismo , Secuencias Reguladoras de Ácidos Nucleicos , Regiones Promotoras Genéticas , Elementos Reguladores de la Transcripción

RESUMEN

We have designed a stochastic model of embryonic neurogenesis in the mouse cerebral cortex, using the formalism of compound Poisson processes. The model accounts for the dynamics of different progenitor cell types and neurons. The expectation and variance of the cell number of each type are derived analytically and illustrated through numerical simulations. The effects of stochastic transition rates between cell types, and stochastic duration of the cell division cycle have been investigated sequentially. The model does not only predict the number of neurons, but also their spatial distribution into deeper and upper cortical layers. The model outputs are consistent with experimental data providing the number of neurons and intermediate progenitors according to embryonic age in control and mutant situations.

Asunto(s)

Corteza Cerebral , Células-Madre Neurales , Neurogénesis , Procesos Estocásticos , Animales , Ratones , Corteza Cerebral/citología , Corteza Cerebral/embriología , Corteza Cerebral/crecimiento & desarrollo , Corteza Cerebral/fisiología , Neurogénesis/fisiología , Células-Madre Neurales/fisiología , Células-Madre Neurales/citología , Modelos Neurológicos , Neuronas/fisiología , Neuronas/citología

RESUMEN

Lawrence et al. report that fetal cortical boundaries are susceptible to morphogenetic stress that regulates a microglia state resembling postnatal, axon-tract associated microglia (ATM). This state performs a newfound function at these boundaries by preventing the formation of cavitary lesions, mediated in part by Spp1-regulated phagocytosis of fibronectin 1.

Asunto(s)

Microglía , Microglía/fisiología , Animales , Humanos , Fagocitosis , Corteza Cerebral/embriología , Corteza Cerebral/citología , Encéfalo/embriología , Encéfalo/fisiología , Fibronectinas/metabolismo

RESUMEN

Thyroid hormones (TH) play critical roles during nervous system development and patients carrying coding variants of MCT8 (monocarboxylate transporter 8) or THRA (thyroid hormone receptor alpha) present a spectrum of neurological phenotypes resulting from perturbed local TH action during early brain development. Recently, human cerebral organoids (hCOs) emerged as powerful in vitro tools for disease modelling recapitulating key aspects of early human cortex development. To begin exploring prospects of this model for thyroid research, we performed a detailed characterization of the spatiotemporal expression of MCT8 and THRA in developing hCOs. Immunostaining showed MCT8 membrane expression in neuronal progenitor cell types including early neuroepithelial cells, radial glia cells (RGCs), intermediate progenitors and outer RGCs. In addition, we detected robust MCT8 protein expression in deep layer and upper layer neurons. Spatiotemporal SLC16A2 mRNA expression, detected by fluorescent in situ hybridization (FISH), was highly concordant with MCT8 protein expression across cortical cell layers. FISH detected THRA mRNA expression already in neuroepithelium before the onset of neurogenesis. THRA mRNA expression remained low in the ventricular zone, increased in the subventricular zone whereas strong THRA expression was observed in excitatory neurons. In combination with a robust up-regulation of known T3 response genes following T3 treatment, these observations show that hCOs provide a promising and experimentally tractable model to probe local TH action during human cortical neurogenesis and eventually to model the consequences of impaired TH function for early cortex development.

Asunto(s)

Corteza Cerebral , Transportadores de Ácidos Monocarboxílicos , Neurogénesis , Organoides , ARN Mensajero , Simportadores , Receptores alfa de Hormona Tiroidea , Femenino , Humanos , Embarazo , Corteza Cerebral/embriología , Corteza Cerebral/metabolismo , Regulación del Desarrollo de la Expresión Génica , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Células-Madre Neurales/metabolismo , Células-Madre Neurales/citología , Neurogénesis/genética , Neuronas/metabolismo , Organoides/metabolismo , Primer Trimestre del Embarazo/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Simportadores/genética , Simportadores/metabolismo , Receptores alfa de Hormona Tiroidea/genética , Receptores alfa de Hormona Tiroidea/metabolismo , Hormonas Tiroideas/metabolismo , Hormonas Tiroideas/genética

RESUMEN

Astrocytes represent a diverse and morphologically complex group of glial cells critical for shaping and maintaining nervous system homeostasis, as well as responding to injuries. Understanding the origins of astroglial heterogeneity, originated from a limited number of progenitors, has been the focus of many studies. Most of these investigations have centered on protoplasmic and pial astrocytes, while the clonal relationship of fibrous astrocytes or juxtavascular astrocytes has remained relatively unexplored. In this study, we sought to elucidate the morphological diversity and clonal distribution of astrocytes across adult cortical layers, with particular emphasis on their ontogenetic origins. Using the StarTrack lineage tracing tool, we explored the characteristics of adult astroglial clones derived from single and specific progenitors at various embryonic stages. Our results revealed a heterogeneous spatial distribution of astroglial clones, characterized by variations in location, clonal size, and rostro-caudal dispersion. While a considerable proportion of clones were confined within specific cortical layers, others displayed sibling cells crossing layer boundaries. Notably, we observed a correlation between clone location and developmental stage at earlier embryonic stages, although this relationship diminished in later stages. Fibrous astrocyte clones were exclusively confined to the corpus callosum. In contrast, protoplasmic or juxtavascular clones were located in either the upper or lower cortical layers, with certain clones displayed sibling cells distributed across both regions. Our findings underscore the developmental origins and spatial distribution of astroglial clones within cortical layers, providing new insights into the interplay between their morphology, clonal sizes, and progenitor heterogeneity.

Asunto(s)

Astrocitos , Astrocitos/citología , Astrocitos/fisiología , Animales , Células Clonales , Corteza Cerebral/citología , Corteza Cerebral/crecimiento & desarrollo , Corteza Cerebral/embriología , Ratones Transgénicos , Ratones , Células-Madre Neurales/citología , Células-Madre Neurales/fisiología

RESUMEN

Sam68 and SLM2 are paralog RNA binding proteins (RBPs) expressed in the cerebral cortex and display similar splicing activities. However, their relative functions during cortical development are unknown. We found that these RBPs exhibit an opposite expression pattern during development. Sam68 expression declines postnatally while SLM2 increases after birth, and this developmental pattern is reinforced by hierarchical control of Sam68 expression by SLM2. Analysis of Sam68:Slm2 double knockout (Sam68:Slm2dko) mice revealed hundreds of exons that respond to joint depletion of these proteins. Moreover, parallel analysis of single and double knockout cortices indicated that exons regulated mainly by SLM2 are characterized by a dynamic splicing pattern during development, whereas Sam68-dependent exons are spliced at relatively constant rates. Dynamic splicing of SLM2-sensitive exons is completely suppressed in the Sam68:Slm2dko developing cortex. Sam68:Slm2dko mice die perinatally with defects in neurogenesis and in neuronal differentiation, and develop a hydrocephalus, consistent with splicing alterations in genes related to these biological processes. Thus, our study reveals that developmental control of separate Sam68 and Slm2 paralog genes encoding homologous RBPs enables the orchestration of a dynamic splicing program needed for brain development and viability, while ensuring a robust redundant mechanism that supports proper cortical development.

Asunto(s)

Corteza Cerebral , Empalme del ARN , Proteínas de Unión al ARN , Animales , Ratones , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Corteza Cerebral/metabolismo , Corteza Cerebral/embriología , Corteza Cerebral/crecimiento & desarrollo , Exones/genética , Regulación del Desarrollo de la Expresión Génica , Ratones Noqueados , Neurogénesis/genética , Neuronas/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo

RESUMEN

OBJECTIVES: Fetuses with late-onset growth restriction (FGR) have a higher risk of suboptimal neurocognitive performance after birth. Previous studies have reported that impaired brain and cortical development can start in utero. The primary aim of this study was to report midline structure growth and cortical development in fetuses with late-onset FGR according to its severity; the secondary aim was to elucidate whether the severity of FGR, as defined by the presence of abnormal Doppler findings, plays a role in affecting brain growth and maturation. METHODS: This was a prospective observational study that included fetuses with late-onset FGR (defined according to the Delphi FGR criteria) undergoing neurosonography between 32 and 34 weeks' gestation. Midline structure (corpus callosum (CC) and cerebellar vermis (CV)) length and cortical development, including the depth of the Sylvian (SF), parieto-occipital (POF) and calcarine (CF) fissures, were compared between late-onset FGR, small-for-gestational-age (SGA) and appropriate-for-gestational-age (AGA) fetuses. Subgroup analysis according to the severity of FGR (normal vs abnormal fetal Doppler) was also performed. Univariate analysis was used to analyze the data. RESULTS: A total of 52 late-onset FGR fetuses with normal Doppler findings, 60 late-onset FGR fetuses with abnormal Doppler findings, 64 SGA fetuses and 100 AGA fetuses were included in the analysis. When comparing AGA controls with SGA fetuses, late-onset FGR fetuses with normal Doppler findings and late-onset FGR fetuses with abnormal Doppler findings, there was a progressive and significant reduction in the absolute values of the following parameters: CC length (median (interquartile range (IQR)), 43.5 (28.9-56.1) mm vs 41.9 (27.8-51.8) mm vs 38.5 (29.1-50.5) mm vs 31.7 (23.8-40.2) mm; K = 26.68; P < 0.0001), SF depth (median (IQR), 14.5 (10.7-16.8) mm vs 12.7 (9.8-15.1) mm vs 11.9 (9.1-13.4) mm vs 8.3 (6.7-10.3) mm; K = 75.82; P < 0.0001), POF depth (median (IQR), 8.6 (6.3-11.1) mm vs 8.1 (5.6-10.4) mm vs 7.8 (6.1-9.3) mm vs 6.6 (4.2-8.0) mm; K = 45.06; P < 0.0001) and CF depth (median (IQR), 9.3 (6.7-11.5) mm vs 8.2 (5.7-10.7) mm vs 7.7 (5.2-9.4) mm vs 6.3 (4.5-7.2) mm; K = 46.14; P < 0.0001). Absolute CV length was significantly higher in AGA fetuses compared with all other groups, although the same progressive pattern was not noted (median (IQR), 24.9 (17.6-29.2) mm vs 21.6 (15.2-26.1) mm vs 19.1 (13.8-25.9) mm vs 21.0 (13.5-25.8) mm; K = 16.72; P = 0.0008). When the neurosonographic variables were corrected for fetal head circumference, a significant difference in the CC length and SF, POF and CF depths, but not CV length, was observed only in late-onset FGR fetuses with abnormal Doppler findings when compared with AGA and SGA fetuses. CONCLUSIONS: Fetuses with late-onset FGR had shorter CC length and delayed cortical development when compared with AGA fetuses. After controlling for fetal head circumference, these differences remained significant only in late-onset FGR fetuses with abnormal Doppler. These findings support the existence of a link between brain development and impaired placental function. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

Asunto(s)

Retardo del Crecimiento Fetal , Ultrasonografía Prenatal , Humanos , Retardo del Crecimiento Fetal/diagnóstico por imagen , Retardo del Crecimiento Fetal/fisiopatología , Femenino , Estudios Prospectivos , Embarazo , Adulto , Edad Gestacional , Recién Nacido Pequeño para la Edad Gestacional , Recién Nacido , Desarrollo Fetal/fisiología , Índice de Severidad de la Enfermedad , Cuerpo Calloso/diagnóstico por imagen , Cuerpo Calloso/embriología , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/embriología , Ultrasonografía Doppler , Tercer Trimestre del Embarazo

RESUMEN

OBJECTIVES: To investigate midbrain growth, including corpus callusum (CC) and cerebellar vermis (CV) and cortical development in late fetal growth restricted (FGR) subclassified according to the umbilical vein blood flow (UVBF) values. METHODS: This was a prospective study on singleton fetuses late FGR with abnormal placental cerebral ratio (PCR). FGR fetuses were further subdivided into normal (≥fifth centile) and abnormal (

Asunto(s)

Retardo del Crecimiento Fetal , Mesencéfalo , Ultrasonografía Prenatal , Venas Umbilicales , Humanos , Femenino , Retardo del Crecimiento Fetal/diagnóstico por imagen , Retardo del Crecimiento Fetal/fisiopatología , Embarazo , Estudios Prospectivos , Estudios Transversales , Venas Umbilicales/diagnóstico por imagen , Adulto , Ultrasonografía Prenatal/métodos , Mesencéfalo/diagnóstico por imagen , Mesencéfalo/irrigación sanguínea , Mesencéfalo/embriología , Desarrollo Fetal/fisiología , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/irrigación sanguínea , Corteza Cerebral/embriología

RESUMEN

The extracellular protein Reelin, expressed by Cajal-Retzius (CR) cells at early stages of cortical development and at late stages by GABAergic interneurons, regulates radial migration and the "inside-out" pattern of positioning. Current models of Reelin functions in corticogenesis focus on early CR cell-derived Reelin in layer I. However, developmental disorders linked to Reelin deficits, such as schizophrenia and autism, are related to GABAergic interneuron-derived Reelin, although its role in migration has not been established. Here we selectively inactivated the Reln gene in CR cells or GABAergic interneurons. We show that CR cells have a major role in the inside-out order of migration, while CR and GABAergic cells sequentially cooperate to prevent invasion of cortical neurons into layer I. Furthermore, GABAergic cell-derived Reelin compensates some features of the reeler phenotype and is needed for the fine tuning of the layer-specific distribution of cortical neurons. In the hippocampus, the inactivation of Reelin in CR cells causes dramatic alterations in the dentate gyrus and mild defects in the hippocampus proper. These findings lead to a model in which both CR and GABAergic cell-derived Reelin cooperate to build the inside-out order of corticogenesis, which might provide a better understanding of the mechanisms involved in the pathogenesis of neuropsychiatric disorders linked to abnormal migration and Reelin deficits.

Asunto(s)

Corteza Cerebral , Proteínas del Tejido Nervioso , Neuronas , Proteína Reelina , Animales , Movimiento Celular , Corteza Cerebral/citología , Corteza Cerebral/embriología , Neuronas GABAérgicas/enzimología , Hipocampo/embriología , Hipocampo/enzimología , Interneuronas/enzimología , Ratones , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/citología , Neuronas/enzimología , Proteína Reelina/genética , Proteína Reelina/metabolismo

RESUMEN

Area-specific axonal projections from the mammalian thalamus shape unique cellular organization in target areas in the adult neocortex. How these axons control neurogenesis and early neuronal fate specification is poorly understood. By using mutant mice lacking the majority of thalamocortical axons, we show that these axons are required for the production and specification of the proper number of layer 4 neurons in primary sensory areas by the neonatal stage. Part of these area-specific roles is played by the thalamus-derived molecule, VGF. Our work reveals that extrinsic cues from sensory thalamic projections have an early role in the formation of cortical cytoarchitecture by enhancing the production and specification of layer 4 neurons.

Asunto(s)

Axones , Tipificación del Cuerpo , Corteza Cerebral , Neurogénesis , Tálamo , Animales , Axones/fisiología , Corteza Cerebral/embriología , Corteza Cerebral/ultraestructura , Ratones , Ratones Mutantes , Vías Nerviosas , Neurogénesis/genética , Neurogénesis/fisiología , Neuronas/fisiología , Tálamo/embriología , Tálamo/ultraestructura

RESUMEN

In the forebrain, ventrally derived oligodendrocyte precursor cells (vOPCs) travel tangentially toward the cortex together with cortical interneurons. Here, we tested in the mouse whether these populations interact during embryogenesis while migrating. By coupling histological analysis of genetic models with live imaging, we show that although they are both attracted by the chemokine Cxcl12, vOPCs and cortical interneurons occupy mutually exclusive forebrain territories enriched in this chemokine. Moreover, first-wave vOPC depletion selectively disrupts the migration and distribution of cortical interneurons. At the cellular level, we found that by promoting unidirectional contact repulsion, first-wave vOPCs steered the migration of cortical interneurons away from the blood vessels to which they were both attracted, thereby allowing interneurons to reach their proper cortical territories.

Asunto(s)

Movimiento Celular , Corteza Cerebral , Interneuronas , Neurogénesis , Células Precursoras de Oligodendrocitos , Animales , Movimiento Celular/genética , Corteza Cerebral/citología , Corteza Cerebral/embriología , Quimiocina CXCL12/metabolismo , Interneuronas/fisiología , Ratones , Modelos Genéticos , Neurogénesis/genética , Células Precursoras de Oligodendrocitos/citología , Células Precursoras de Oligodendrocitos/fisiología

RESUMEN

Coordinated programs of gene expression drive brain development. It is unclear which transcriptional programs, in which cell-types, are affected in neuropsychiatric disorders such as schizophrenia. Here we integrate human genetics with transcriptomic data from differentiation of human embryonic stem cells into cortical excitatory neurons. We identify transcriptional programs expressed during early neurogenesis in vitro and in human foetal cortex that are down-regulated in DLG2-/- lines. Down-regulation impacted neuronal differentiation and maturation, impairing migration, morphology and action potential generation. Genetic variation in these programs is associated with neuropsychiatric disorders and cognitive function, with associated variants predominantly concentrated in loss-of-function intolerant genes. Neurogenic programs also overlap schizophrenia GWAS enrichment previously identified in mature excitatory neurons, suggesting that pathways active during prenatal cortical development may also be associated with mature neuronal dysfunction. Our data from human embryonic stem cells, when combined with analysis of available foetal cortical gene expression data, de novo rare variants and GWAS statistics for neuropsychiatric disorders and cognition, reveal a convergence on transcriptional programs regulating excitatory cortical neurogenesis.

Asunto(s)

Corteza Cerebral/embriología , Regulación del Desarrollo de la Expresión Génica , Guanilato-Quinasas/genética , Neurogénesis , Proteínas Supresoras de Tumor/genética , Animales , Diferenciación Celular , Corteza Cerebral/citología , Corteza Cerebral/metabolismo , Femenino , Técnicas de Silenciamiento del Gen , Predisposición Genética a la Enfermedad , Guanilato-Quinasas/metabolismo , Células Madre Embrionarias Humanas/metabolismo , Humanos , Trastornos Mentales/genética , Neurogénesis/genética , Neurogénesis/fisiología , Neuronas , Embarazo , Esquizofrenia/genética , Transcriptoma , Proteínas Supresoras de Tumor/metabolismo

RESUMEN

The human cortex contains inhibitory interneurons derived from the medial ganglionic eminence (MGE), a germinal zone in the embryonic ventral forebrain. How this germinal zone generates sufficient interneurons for the human brain remains unclear. We found that the human MGE (hMGE) contains nests of proliferative neuroblasts with ultrastructural and transcriptomic features that distinguish them from other progenitors in the hMGE. When dissociated hMGE cells are transplanted into the neonatal mouse brain, they reform into nests containing proliferating neuroblasts that generate young neurons that migrate extensively into the mouse forebrain and mature into different subtypes of functional interneurons. Together, these results indicate that the nest organization and sustained proliferation of neuroblasts in the hMGE provide a mechanism for the extended production of interneurons for the human forebrain.

Asunto(s)

Interneuronas/fisiología , Eminencia Media/embriología , Células-Madre Neurales/fisiología , Neurogénesis , Prosencéfalo/citología , Animales , Animales Recién Nacidos , Movimiento Celular , Proliferación Celular , Corteza Cerebral/citología , Corteza Cerebral/embriología , Corteza Cerebral/crecimiento & desarrollo , Neuronas GABAérgicas/citología , Neuronas GABAérgicas/fisiología , Perfilación de la Expresión Génica , Edad Gestacional , Humanos , Interneuronas/citología , Eminencia Media/citología , Eminencia Media/crecimiento & desarrollo , Ratones , Células-Madre Neurales/trasplante , Prosencéfalo/embriología , Prosencéfalo/crecimiento & desarrollo , Trasplante Heterólogo