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1.
Cell ; 155(2): 333-44, 2013 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-24120134

RESUMO

Primary cilia are key sensory organelles that are thought to be disassembled prior to mitosis. Inheritance of the mother centriole, which nucleates the primary cilium, in relation to asymmetric daughter cell behavior has previously been studied. However, the fate of the ciliary membrane upon cell division is unknown. Here, we followed the ciliary membrane in dividing embryonic neocortical stem cells and cultured cells. Ciliary membrane attached to the mother centriole was endocytosed at mitosis onset, persisted through mitosis at one spindle pole, and was asymmetrically inherited by one daughter cell, which retained stem cell character. This daughter re-established a primary cilium harboring an activated signal transducer earlier than the noninheriting daughter. Centrosomal association of ciliary membrane in dividing neural stem cells decreased at late neurogenesis when these cells differentiate. Our data imply that centrosome-associated ciliary membrane acts as a determinant for the temporal-spatial control of ciliogenesis.


Assuntos
Divisão Celular , Cílios/metabolismo , Células-Tronco Neurais/citologia , Fatores de Ribosilação do ADP , Animais , Centríolos/metabolismo , Centrossomo/metabolismo , Células HEK293 , Humanos , Camundongos , Mitose , Células-Tronco Neurais/metabolismo
2.
Annu Rev Cell Dev Biol ; 30: 465-502, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25000993

RESUMO

Neural stem and progenitor cells have a central role in the development and evolution of the mammalian neocortex. In this review, we first provide a set of criteria to classify the various types of cortical stem and progenitor cells. We then discuss the issue of cell polarity, as well as specific subcellular features of these cells that are relevant for their modes of division and daughter cell fate. In addition, cortical stem and progenitor cell behavior is placed into a tissue context, with consideration of extracellular signals and cell-cell interactions. Finally, the differences across species regarding cortical stem and progenitor cells are dissected to gain insight into key developmental and evolutionary mechanisms underlying neocortex expansion.


Assuntos
Neocórtex/crescimento & desenvolvimento , Neurogênese/fisiologia , Animais , Divisão Celular Assimétrica , Compartimento Celular , Linhagem da Célula , Membrana Celular/fisiologia , Núcleo Celular/fisiologia , Polaridade Celular , Líquido Cefalorraquidiano/fisiologia , Humanos , Junções Intercelulares/fisiologia , Ventrículos Laterais/embriologia , Lipídeos de Membrana/metabolismo , Microglia/fisiologia , Mitose , Neocórtex/citologia , Neocórtex/embriologia , Células-Tronco Neurais/classificação , Células-Tronco Neurais/fisiologia , Células Neuroepiteliais/citologia , Células Neuroepiteliais/fisiologia , Neurônios/fisiologia , Organelas/fisiologia , Especificidade da Espécie
3.
Development ; 151(4)2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38369736

RESUMO

The generation of neurons in the developing neocortex is a major determinant of neocortex size. Crucially, the increase in cortical neuron numbers in the primate lineage, notably in the upper-layer neurons, contributes to increased cognitive abilities. Here, we review major evolutionary changes affecting the apical progenitors in the ventricular zone and focus on the key germinal zone constituting the foundation of neocortical neurogenesis in primates, the outer subventricular zone (OSVZ). We summarize characteristic features of the OSVZ and its key stem cell type, the basal (or outer) radial glia. Next, we concentrate on primate-specific and human-specific genes, expressed in OSVZ-progenitors, the ability of which to amplify these progenitors by targeting the regulation of the cell cycle ultimately underlies the evolutionary increase in upper-layer neurons. Finally, we address likely differences in neocortical development between present-day humans and Neanderthals that are based on human-specific amino acid substitutions in proteins operating in cortical progenitors.


Assuntos
Neocórtex , Neuroglia , Animais , Humanos , Neuroglia/metabolismo , Neocórtex/metabolismo , Neurônios/metabolismo , Células-Tronco , Primatas/genética , Neurogênese/genética
4.
EMBO J ; 40(19): e108041, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34431536

RESUMO

The role of WNT/ß-catenin signalling in mouse neocortex development remains ambiguous. Most studies demonstrate that WNT/ß-catenin regulates progenitor self-renewal but others suggest it can also promote differentiation. Here we explore the role of WNT/STOP signalling, which stabilizes proteins during G2/M by inhibiting glycogen synthase kinase (GSK3)-mediated protein degradation. We show that mice mutant for cyclin Y and cyclin Y-like 1 (Ccny/l1), key regulators of WNT/STOP signalling, display reduced neurogenesis in the developing neocortex. Specifically, basal progenitors, which exhibit delayed cell cycle progression, were drastically decreased. Ccny/l1-deficient apical progenitors show reduced asymmetric division due to an increase in apical-basal astral microtubules. We identify the neurogenic transcription factors Sox4 and Sox11 as direct GSK3 targets that are stabilized by WNT/STOP signalling in basal progenitors during mitosis and that promote neuron generation. Our work reveals that WNT/STOP signalling drives cortical neurogenesis and identifies mitosis as a critical phase for neural progenitor fate.


Assuntos
Mitose , Neocórtex/embriologia , Neocórtex/metabolismo , Neurogênese , Via de Sinalização Wnt , Sequência de Aminoácidos , Animais , Biomarcadores , Ciclo Celular , Diferenciação Celular/genética , Ciclinas/genética , Ciclinas/metabolismo , Embrião de Mamíferos , Imunofluorescência , Expressão Gênica , Quinase 3 da Glicogênio Sintase/metabolismo , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Mitose/genética , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neurogênese/genética , Fosforilação , Fatores de Transcrição SOXC/genética , Fatores de Transcrição SOXC/metabolismo
5.
EMBO J ; 40(13): e107093, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33938018

RESUMO

Neocortex expansion during human evolution provides a basis for our enhanced cognitive abilities. Yet, which genes implicated in neocortex expansion are actually responsible for higher cognitive abilities is unknown. The expression of human-specific ARHGAP11B in embryonic/foetal mouse, ferret and marmoset neocortex was previously found to promote basal progenitor proliferation, upper-layer neuron generation and neocortex expansion during development, features commonly thought to contribute to increased cognitive abilities. However, a key question is whether this phenotype persists into adulthood and if so, whether cognitive abilities are indeed increased. Here, we generated a transgenic mouse line with physiological ARHGAP11B expression that exhibits increased neocortical size and upper-layer neuron numbers persisting into adulthood. Adult ARHGAP11B-transgenic mice showed altered neurobehaviour, notably increased memory flexibility and a reduced anxiety level. Our data are consistent with the notion that neocortex expansion by ARHGAP11B, a gene implicated in human evolution, underlies some of the altered neurobehavioural features observed in the transgenic mice, such as the increased memory flexibility, a neocortex-associated trait, with implications for the increase in cognitive abilities during human evolution.


Assuntos
Proteínas Ativadoras de GTPase/metabolismo , Memória/fisiologia , Neocórtex/metabolismo , Neocórtex/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Animais , Ansiedade/metabolismo , Ansiedade/fisiopatologia , Evolução Biológica , Proliferação de Células/fisiologia , Cognição/fisiologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurogênese/fisiologia
6.
Brain ; 147(1): 56-80, 2024 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-37703310

RESUMO

Integrating independent but converging lines of research on brain function and neurodevelopment across scales, this article proposes that serotonin 2A receptor (5-HT2AR) signalling is an evolutionary and developmental driver and potent modulator of the macroscale functional organization of the human cerebral cortex. A wealth of evidence indicates that the anatomical and functional organization of the cortex follows a unimodal-to-transmodal gradient. Situated at the apex of this processing hierarchy-where it plays a central role in the integrative processes underpinning complex, human-defining cognition-the transmodal cortex has disproportionately expanded across human development and evolution. Notably, the adult human transmodal cortex is especially rich in 5-HT2AR expression and recent evidence suggests that, during early brain development, 5-HT2AR signalling on neural progenitor cells stimulates their proliferation-a critical process for evolutionarily-relevant cortical expansion. Drawing on multimodal neuroimaging and cross-species investigations, we argue that, by contributing to the expansion of the human cortex and being prevalent at the apex of its hierarchy in the adult brain, 5-HT2AR signalling plays a major role in both human cortical expansion and functioning. Owing to its unique excitatory and downstream cellular effects, neuronal 5-HT2AR agonism promotes neuroplasticity, learning and cognitive and psychological flexibility in a context-(hyper)sensitive manner with therapeutic potential. Overall, we delineate a dual role of 5-HT2ARs in enabling both the expansion and modulation of the human transmodal cortex.


Assuntos
Córtex Cerebral , Receptor 5-HT2A de Serotonina , Adulto , Humanos , Encéfalo , Córtex Cerebral/fisiologia , Cognição/fisiologia , Neuroimagem
7.
Nature ; 574(7778): 418-422, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31619793

RESUMO

The human brain has undergone substantial change since humans diverged from chimpanzees and the other great apes1,2. However, the genetic and developmental programs that underlie this divergence are not fully understood. Here we have analysed stem cell-derived cerebral organoids using single-cell transcriptomics and accessible chromatin profiling to investigate gene-regulatory changes that are specific to humans. We first analysed cell composition and reconstructed differentiation trajectories over the entire course of human cerebral organoid development from pluripotency, through neuroectoderm and neuroepithelial stages, followed by divergence into neuronal fates within the dorsal and ventral forebrain, midbrain and hindbrain regions. Brain-region composition varied in organoids from different iPSC lines, but regional gene-expression patterns remained largely reproducible across individuals. We analysed chimpanzee and macaque cerebral organoids and found that human neuronal development occurs at a slower pace relative to the other two primates. Using pseudotemporal alignment of differentiation paths, we found that human-specific gene expression resolved to distinct cell states along progenitor-to-neuron lineages in the cortex. Chromatin accessibility was dynamic during cortex development, and we identified divergence in accessibility between human and chimpanzee that correlated with human-specific gene expression and genetic change. Finally, we mapped human-specific expression in adult prefrontal cortex using single-nucleus RNA sequencing analysis and identified developmental differences that persist into adulthood, as well as cell-state-specific changes that occur exclusively in the adult brain. Our data provide a temporal cell atlas of great ape forebrain development, and illuminate dynamic gene-regulatory features that are unique to humans.


Assuntos
Encéfalo , Genômica , Organoides/citologia , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/fisiologia , Animais , Evolução Biológica , Encéfalo/citologia , Encéfalo/embriologia , Encéfalo/fisiologia , Humanos , Macaca , Pan troglodytes , Análise de Célula Única , Especificidade da Espécie
8.
Nature ; 567(7746): 113-117, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30787442

RESUMO

The expansion of brain size is accompanied by a relative enlargement of the subventricular zone during development. Epithelial-like neural stem cells divide in the ventricular zone at the ventricles of the embryonic brain, self-renew and generate basal progenitors1 that delaminate and settle in the subventricular zone in enlarged brain regions2. The length of time that cells stay in the subventricular zone is essential for controlling further amplification and fate determination. Here we show that the interphase centrosome protein AKNA has a key role in this process. AKNA localizes at the subdistal appendages of the mother centriole in specific subtypes of neural stem cells, and in almost all basal progenitors. This protein is necessary and sufficient to organize centrosomal microtubules, and promote their nucleation and growth. These features of AKNA are important for mediating the delamination process in the formation of the subventricular zone. Moreover, AKNA regulates the exit from the subventricular zone, which reveals the pivotal role of centrosomal microtubule organization in enabling cells to both enter and remain in the subventricular zone. The epithelial-to-mesenchymal transition is also regulated by AKNA in other epithelial cells, demonstrating its general importance for the control of cell delamination.


Assuntos
Centrossomo/metabolismo , Proteínas de Ligação a DNA/metabolismo , Ventrículos Laterais/citologia , Ventrículos Laterais/embriologia , Microtúbulos/metabolismo , Neurogênese , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Animais , Movimento Celular , Células Cultivadas , Células Epiteliais/metabolismo , Transição Epitelial-Mesenquimal , Humanos , Junções Intercelulares/metabolismo , Interfase , Ventrículos Laterais/anatomia & histologia , Glândulas Mamárias Animais/citologia , Camundongos , Tamanho do Órgão , Organoides/citologia
9.
EMBO Rep ; 23(11): e54728, 2022 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-36098218

RESUMO

The human-specific gene ARHGAP11B has been implicated in human neocortex expansion. However, the extent of ARHGAP11B's contribution to this expansion during hominid evolution is unknown. Here we address this issue by genetic manipulation of ARHGAP11B levels and function in chimpanzee and human cerebral organoids. ARHGAP11B expression in chimpanzee cerebral organoids doubles basal progenitor levels, the class of cortical progenitors with a key role in neocortex expansion. Conversely, interference with ARHGAP11B's function in human cerebral organoids decreases basal progenitors down to the chimpanzee level. Moreover, ARHGAP11A or ARHGAP11B rescue experiments in ARHGAP11A plus ARHGAP11B double-knockout human forebrain organoids indicate that lack of ARHGAP11B, but not of ARHGAP11A, decreases the abundance of basal radial glia-the basal progenitor type thought to be of particular relevance for neocortex expansion. Taken together, our findings demonstrate that ARHGAP11B is necessary and sufficient to ensure the elevated basal progenitor levels that characterize the fetal human neocortex, suggesting that this human-specific gene was a major contributor to neocortex expansion during human evolution.


Assuntos
Hominidae , Neocórtex , Células-Tronco Neurais , Animais , Humanos , Células-Tronco Neurais/metabolismo , Organoides/metabolismo , Hominidae/metabolismo , Pan troglodytes/genética , Pan troglodytes/metabolismo , Neocórtex/metabolismo , Neurogênese/genética , Proteínas Ativadoras de GTPase/genética , Proteínas Ativadoras de GTPase/metabolismo
10.
EMBO J ; 38(2)2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30523147

RESUMO

Proper temporal and spatial activation of stem cells relies on highly coordinated cell signaling. The primary cilium is the sensory organelle that is responsible for transmitting extracellular signals into a cell. Primary cilium size, architecture, and assembly-disassembly dynamics are under rigid cell cycle-dependent control. Using mouse incisor tooth epithelia as a model, we show that ciliary dynamics in stem cells require the proper functions of a cholesterol-binding membrane glycoprotein, Prominin-1 (Prom1/CD133), which controls sequential recruitment of ciliary membrane components, histone deacetylase, and transcription factors. Nuclear translocation of Prom1 and these molecules is particularly evident in transit amplifying cells, the immediate derivatives of stem cells. The absence of Prom1 impairs ciliary dynamics and abolishes the growth stimulation effects of sonic hedgehog (SHH) treatment, resulting in the disruption of stem cell quiescence maintenance and activation. We propose that Prom1 is a key regulator ensuring appropriate response of stem cells to extracellular signals, with important implications for development, regeneration, and diseases.


Assuntos
Antígeno AC133/metabolismo , Cílios/metabolismo , Incisivo/citologia , Antígeno AC133/genética , Animais , Núcleo Celular/metabolismo , Células Cultivadas , Humanos , Incisivo/metabolismo , Camundongos , Modelos Biológicos , Mutagênese Sítio-Dirigida , Transporte Proteico , Transdução de Sinais , Células-Tronco/citologia , Células-Tronco/metabolismo
11.
Trop Anim Health Prod ; 55(1): 42, 2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36656383

RESUMO

According to previous studies, lamb mortality is high in the Ethiopian highlands. The present study aims to evaluate the execution of preventive sheep herd health management practices with respect to if, and how, such practices are linked to occurrence of lamb mortality. Interviews were performed with 74 sheep-owning households participating in a capacity development program on livestock and 69 households not participating in such program. To evaluate the impact of combinations of performed practices, a scoring system was developed-the households retrieved a higher score the more desired routines were accomplished. To identify which practices had the highest impact on lamb mortality, a similar score was calculated for each phase of the sheep reproductive year, creating sub-scores for each phase. The results showed a significant (p < 0.05) negative correlation between the total number of performed practices and occurrence of lamb mortality, indicating a lower occurrence of lamb mortality the more desired practices implemented. Further analysis of sub-scores showed significant (p < 0.05) negative correlations between a higher number of performed desired practices during gestation period and during lambing. Conclusively, the study indicates that preventive herd management routines are beneficial for lamb survival, foremost when enforced during the gestation period and around lambing-hence, this is where to focus future interventions.


Assuntos
Doenças dos Ovinos , Animais , Ovinos , Etiópia/epidemiologia , Doenças dos Ovinos/prevenção & controle , Doenças dos Ovinos/epidemiologia , Reprodução
12.
Traffic ; 20(1): 39-60, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30328220

RESUMO

Prominin-1 is a cell surface biomarker that allows the identification of stem and cancer stem cells from different organs. It is also expressed in several differentiated epithelial and non-epithelial cells. Irrespective of the cell type, prominin-1 is associated with plasma membrane protrusions. Here, we investigate its impact on the architecture of membrane protrusions using microvilli of Madin-Darby canine kidney cells as the main model. Our high-resolution analysis revealed that upon the overexpression of prominin-1 the number of microvilli and clusters of them increased. Microvilli with branched and/or knob-like morphologies were observed and stimulated by mutations in the ganglioside-binding site of prominin-1. The altered phenotypes were caused by the interaction of prominin-1 with phosphoinositide 3-kinase and Arp2/3 complex. Mutation of tyrosine 828 of prominin-1 impaired its phosphorylation and thereby inhibited the aforementioned interactions abolishing altered microvilli. This suggests that the interplay of prominin-1-ganglioside membrane complexes, phosphoinositide 3-kinase and cytoskeleton components regulates microvillar architecture. Lastly, the expression of prominin-1 and its mutants modified the structure of filopodia emerging from fibroblast-like cells and silencing human prominin-1 in primary hematopoietic stem cells resulted in the loss of uropod-associated microvilli. Altogether, these findings strengthen the role of prominin-1 as an organizer of cellular protrusions.


Assuntos
Antígeno AC133/metabolismo , Microvilosidades/metabolismo , Antígeno AC133/química , Antígeno AC133/genética , Animais , Sítios de Ligação , Células CHO , Células Cultivadas , Cricetinae , Cricetulus , Cães , Gangliosídeos/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Humanos , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos C57BL , Microvilosidades/ultraestrutura , Mutação , Fosfatidilinositol 3-Quinases/metabolismo , Ligação Proteica
13.
J Neurosci ; 40(8): 1766-1777, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-31953373

RESUMO

Open spina bifida (OSB) is one of the most prevalent congenital malformations of the CNS that often leads to severe disabilities. Previous studies reported the volume and thickness of the neocortex to be altered in children and adolescents diagnosed with OSB. Until now, the onset and the underlying cause of the atypical neocortex organization in OSB patients remain largely unknown. To examine the effects of OSB on fetal neocortex development, we analyzed human fetuses of both sexes diagnosed with OSB between 11 and 15 weeks of gestation by immunofluorescence for established neuronal and neural progenitor marker proteins and compared the results with healthy controls of the same, or very similar, gestational age. Our data indicate that neocortex development in OSB fetuses is altered as early as 11 weeks of gestation. We observed a marked reduction in the radial thickness of the OSB neocortex, which appears to be attributable to a massive decrease in the number of deep- and upper-layer neurons per field, and found a marked reduction in the number of basal progenitors (BPs) per field in the OSB neocortex, consistent with an impairment of cortical neurogenesis underlying the neuronal decrease in OSB fetuses. Moreover, our data suggest that the decrease in BP number in the OSB neocortex may be associated with BPs spending a lesser proportion of their cell cycle in M-phase. Together, our findings expand our understanding of the pathophysiology of OSB and support the need for an early fetal therapy (i.e., in the first trimester of pregnancy).SIGNIFICANCE STATEMENT Open spina bifida (OSB) is one of the most prevalent congenital malformations of the CNS. This study provides novel data on neocortex development of human OSB fetuses. Our data indicate that neocortex development in OSB fetuses is altered as early as 11 weeks of gestation. We observed a marked reduction in the radial thickness of the OSB neocortex, which appears to be attributable a decrease in the number of deep- and upper-layer neurons per field, and found a marked reduction in the number of basal progenitors per field, indicating that impaired neurogenesis underlies the neuronal decrease in OSB fetuses. Our findings support the need for an early fetal therapy and expand our understanding of the pathophysiology of OSB.


Assuntos
Córtex Cerebral/embriologia , Desenvolvimento Embrionário/fisiologia , Células-Tronco Neurais , Neurogênese/fisiologia , Neurônios/patologia , Espinha Bífida Cística/embriologia , Córtex Cerebral/patologia , Feminino , Idade Gestacional , Humanos , Gravidez , Primeiro Trimestre da Gravidez
14.
J Biol Chem ; 295(18): 6007-6022, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32201384

RESUMO

Prominins (proms) are transmembrane glycoproteins conserved throughout the animal kingdom. They are associated with plasma membrane protrusions, such as primary cilia, as well as extracellular vesicles derived thereof. Primary cilia host numerous signaling pathways affected in diseases known as ciliopathies. Human PROM1 (CD133) is detected in both somatic and cancer stem cells and is also expressed in terminally differentiated epithelial and photoreceptor cells. Genetic mutations in the PROM1 gene result in retinal degeneration by impairing the proper formation of the outer segment of photoreceptors, a modified cilium. Here, we investigated the impact of proms on two distinct examples of ciliogenesis. First, we demonstrate that the overexpression of a dominant-negative mutant variant of human PROM1 (i.e. mutation Y819F/Y828F) significantly decreases ciliary length in Madin-Darby canine kidney cells. These results contrast strongly to the previously observed enhancing effect of WT PROM1 on ciliary length. Mechanistically, the mutation impeded the interaction of PROM1 with ADP-ribosylation factor-like protein 13B, a key regulator of ciliary length. Second, we observed that in vivo knockdown of prom3 in zebrafish alters the number and length of monocilia in the Kupffer's vesicle, resulting in molecular and anatomical defects in the left-right asymmetry. These distinct loss-of-function approaches in two biological systems reveal that prom proteins are critical for the integrity and function of cilia. Our data provide new insights into ciliogenesis and might be of particular interest for investigations of the etiologies of ciliopathies.


Assuntos
Antígeno AC133/metabolismo , Cílios/metabolismo , Peixe-Zebra , Antígeno AC133/química , Antígeno AC133/genética , Animais , Cães , Regulação para Baixo , Regulação da Expressão Gênica no Desenvolvimento , Espaço Intracelular/metabolismo , Células de Kupffer/citologia , Células Madin Darby de Rim Canino , Mutação , Transporte Proteico , Tirosina
15.
EMBO J ; 36(17): 2642-2658, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28765163

RESUMO

The generation of neocortical neurons from neural progenitor cells (NPCs) is primarily controlled by transcription factors binding to DNA in the context of chromatin. To understand the complex layer of regulation that orchestrates different NPC types from the same DNA sequence, epigenome maps with cell type resolution are required. Here, we present genomewide histone methylation maps for distinct neural cell populations in the developing mouse neocortex. Using different chromatin features, we identify potential novel regulators of cortical NPCs. Moreover, we identify extensive H3K27me3 changes between NPC subtypes coinciding with major developmental and cell biological transitions. Interestingly, we detect dynamic H3K27me3 changes on promoters of several crucial transcription factors, including the basal progenitor regulator Eomes We use catalytically inactive Cas9 fused with the histone methyltransferase Ezh2 to edit H3K27me3 at the Eomes locus in vivo, which results in reduced Tbr2 expression and lower basal progenitor abundance, underscoring the relevance of dynamic H3K27me3 changes during neocortex development. Taken together, we provide a rich resource of neocortical histone methylation data and outline an approach to investigate its contribution to the regulation of selected genes during neocortical development.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Histonas/genética , Neocórtex/metabolismo , Células-Tronco Neurais/fisiologia , Animais , Epigênese Genética , Perfilação da Expressão Gênica , Genoma , Metilação , Camundongos Transgênicos , Neurogênese/fisiologia
16.
Development ; 145(20)2018 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-30266827

RESUMO

A specific subpopulation of neural progenitor cells, the basal radial glial cells (bRGCs) of the outer subventricular zone (OSVZ), are thought to have a key role in the evolutionary expansion of the mammalian neocortex. In the developing lissencephalic mouse neocortex, bRGCs exist at low abundance and show significant molecular differences from bRGCs in developing gyrencephalic species. Here, we demonstrate that the developing mouse medial neocortex (medNcx), in contrast to the canonically studied lateral neocortex (latNcx), exhibits an OSVZ and an abundance of bRGCs similar to that in developing gyrencephalic neocortex. Unlike bRGCs in developing mouse latNcx, the bRGCs in medNcx exhibit human bRGC-like gene expression, including expression of Hopx, a human bRGC marker. Disruption of Hopx expression in mouse embryonic medNcx and forced Hopx expression in mouse embryonic latNcx demonstrate that Hopx is required and sufficient, respectively, for bRGC abundance as found in the developing gyrencephalic neocortex. Taken together, our data identify a novel bRGC subpopulation in developing mouse medNcx that is highly related to bRGCs of developing gyrencephalic neocortex.


Assuntos
Células Ependimogliais/metabolismo , Proteínas de Homeodomínio/metabolismo , Neocórtex/citologia , Neocórtex/embriologia , Animais , Sistemas CRISPR-Cas/genética , Proliferação de Células , Embrião de Mamíferos/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Ventrículos Laterais/embriologia , Camundongos Endogâmicos C57BL , Neocórtex/metabolismo , Fator de Transcrição PAX6/metabolismo , Células-Tronco/citologia
17.
Biochem Soc Trans ; 49(5): 1997-2006, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34397081

RESUMO

The mammalian neocortex is the seat of higher cognitive functions, such as thinking and language in human. A hallmark of the neocortex are the cortical neurons, which are generated from divisions of neural progenitor cells (NPCs) during development, and which constitute a key feature of the well-organized layered structure of the neocortex. Proper formation of neocortex structure requires an orchestrated cellular behavior of different cortical NPCs during development, especially during the process of cortical neurogenesis. Here, we review the great diversity of NPCs and their contribution to the development of the neocortex. First, we review the categorization of NPCs into different classes and types based on their cell biological features, and discuss recent advances in characterizing marker expression and cell polarity features in the different types of NPCs. Second, we review the different modes of cell divisions that NPCs undergo and discuss the importance of the balance between proliferation and differentiation of NPCs in neocortical development. Third, we review the different proliferative capacities among different NPC types and among the same type of NPC in different mammalian species. Dissecting the differences between NPC types and differences among mammalian species is beneficial to further understand the development and the evolutionary expansion of the neocortex and may open up new therapeutic avenues for neurodevelopmental and psychiatric disorders.


Assuntos
Neocórtex/citologia , Neocórtex/crescimento & desenvolvimento , Células-Tronco Neurais/citologia , Neurogênese/fisiologia , Neurônios/citologia , Animais , Evolução Biológica , Divisão Celular/fisiologia , Polaridade Celular/fisiologia , Humanos , Células-Tronco Neurais/classificação , Células-Tronco Neurais/metabolismo , Neurônios/metabolismo , Transdução de Sinais/fisiologia
18.
EMBO Rep ; 20(10): e47880, 2019 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-31469223

RESUMO

Microinjection into single cells in brain tissue is a powerful technique to study and manipulate neural stem cells. However, such microinjection requires expertise and is a low-throughput process. We developed the "Autoinjector", a robot that utilizes images from a microscope to guide a microinjection needle into tissue to deliver femtoliter volumes of liquids into single cells. The Autoinjector enables microinjection of hundreds of cells within a single organotypic slice, resulting in an overall yield that is an order of magnitude greater than manual microinjection. The Autoinjector successfully targets both apical progenitors (APs) and newborn neurons in the embryonic mouse and human fetal telencephalon. We used the Autoinjector to systematically study gap-junctional communication between neural progenitors in the embryonic mouse telencephalon and found that apical contact is a characteristic feature of the cells that are part of a gap junction-coupled cluster. The throughput and versatility of the Autoinjector will render microinjection an accessible high-performance single-cell manipulation technique and will provide a powerful new platform for performing single-cell analyses in tissue for bioengineering and biophysics applications.


Assuntos
Encéfalo/citologia , Microinjeções , Robótica , Análise de Célula Única , Animais , Automação , Comunicação Celular , Linhagem da Célula , Humanos , Processamento de Imagem Assistida por Computador , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/citologia , Neurogênese , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Telencéfalo/citologia , Telencéfalo/embriologia
19.
Rev Sci Tech ; 40(2): 555-566, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34542094

RESUMO

The veterinary profession has time and again successfully adapted to new challenges and developments, with considerable evolution of the skills needed. Different contexts, production systems and societal requirements continue to shape the profession, resulting in an increasing demand for specialisation, interdisciplinary collaboration along value chains, and preparedness for the omnipresent risk of emerging diseases. To keep up with changes, new insights, advances in research and novel ways to address challenges, continuing professional development (CPD) and the adaptation and updating of the veterinary curriculum have been essential to maintain and enhance the quality and performance of Veterinary Services. This paper reviews actors involved in the provision of Veterinary Services and discusses how vital CPD is in addressing current and future challenges, by focusing on veterinarians and allied veterinary professionals. The authors examine how providers of CPD contribute to the system and how the internal and external factors of a cohort or individual affect the quality and impact of capacity development. The paper further examines the landscape of veterinary CPD in terms of organisational structures, pedagogical approaches, the transition from input- to outcome-based learning, modern delivery tools, and the demands on the different actors involved in the delivery of animal health services. The authors conclude that CPD is essential if the quality of Veterinary Services is to keep pace with the ever-increasing and evolving demands of the 21st century. A CPD programme should therefore be constructed in a way that is tailored to the needs of veterinary professionals and to the requirements of their workplace, whether they work with animal keepers, livestock value chains, national governments or international regulatory bodies. An optimised and successful veterinary sector requires an evidencebased CPD programme that keeps those professionals who are involved in the delivery of animal health services both competent and relevant in a changing world.


La profession vétérinaire s'est adaptée à maintes reprises et avec succès à de nouveaux défis et évolutions qui ont nécessité la mobilisation d'un grand nombre de compétences nouvelles. La diversité des contextes, des systèmes de production et des exigences sociétales impose à la profession vétérinaire des transformations continues, avec pour conséquences une demande croissante de spécialisation et de collaborations interdisciplinaires le long des chaînes de valeur et la nécessité de mieux se préparer au risque omniprésent de maladies émergentes. Face aux changements intervenus, aux nouvelles connaissances, aux progrès de la recherche et aux nouvelles manières de relever les défis, la formation professionnelle continue (FPC) et l'adaptation et actualisation des cursus d'enseignement vétérinaire ont joué un rôle déterminant pour maintenir et améliorer la qualité et les performances des Services vétérinaires. Les auteurs font le point sur les divers prestataires de services vétérinaires et examinent le rôle essentiel de la FPC pour relever les défis actuels et futurs, en mettant l'accent sur les vétérinaires et les professions connexes travaillant en lien avec les vétérinaires. Ils analysent la contribution des fournisseurs de FPC au système de santé animale, ainsi que l'influence sur la qualité et l'impact du renforcement des capacités d'un certain nombre de facteurs internes et externes à l'échelle des cohortes ou des individus. Les auteurs décrivent également le paysage de la FPC dans le domaine vétérinaire et plus particulièrement les structures organisationnelles, les approches pédagogiques, la transition d'un apprentissage axé sur les contenus à un apprentissage axé sur les résultats, les outils modernes de formation et les exigences imposées aux différents prestataires de services de santé animale dans un monde en constante évolution. En conclusion, les auteurs insistent sur l'importance cruciale de mettre en place des dispositifs de formation professionnelle continue destinés au secteur vétérinaire, afin que la qualité des services fournis soit à la hauteur des exigences croissantes et en constante évolution du 21e siècle. Les programmes de FPC doivent donc être conçus en veillant à s'adapter aux besoins des vétérinaires et des professionnels des domaines connexes concernant les compétences spécifiques qu'ils doivent déployer en fonction des exigences de leur activité, qu'ils travaillent auprès des gardiens d'animaux, des professionnels des filières issues de l'élevage, des gouvernements nationaux ou des organismes internationaux chargés de l'élaboration de normes. Un secteur vétérinaire optimisé et performant nécessite un programme de FPC fondé sur des données concrètes afin que les vétérinaires et les autres prestataires de services de santé animale puissent maintenir leur niveau de compétences ainsi que la pertinence de leurs interventions au regard des exigences évolutives d'un monde en pleine transformation. La profession vétérinaire s'est adaptée à maintes reprises et avec succès à de nouveaux défis et évolutions qui ont nécessité la mobilisation d'un grand nombre de compétences nouvelles. La diversité des contextes, des systèmes de production et des exigences sociétales impose à la profession vétérinaire des transformations continues, avec pour conséquences une demande croissante de spécialisation et de collaborations interdisciplinaires le long des chaînes de valeur et la nécessité de mieux se préparer au risque omniprésent de maladies émergentes. Face aux changements intervenus, aux nouvelles connaissances, aux progrès de la recherche et aux nouvelles manières de relever les défis, la formation professionnelle continue (FPC) et l'adaptation et actualisation des cursus d'enseignement vétérinaire ont joué un rôle déterminant pour maintenir et améliorer la qualité et les performances des Services vétérinaires. Les auteurs font le point sur les divers prestataires de services vétérinaires et examinent le rôle essentiel de la FPC pour relever les défis actuels et futurs, en mettant l'accent sur les vétérinaires et les professions connexes travaillant en lien avec les vétérinaires. Ils analysent la contribution des fournisseurs de FPC au système de santé animale, ainsi que l'influence sur la qualité et l'impact du renforcement des capacités d'un certain nombre de facteurs internes et externes à l'échelle des cohortes ou des individus. Les auteurs décrivent également le paysage de la FPC dans le domaine vétérinaire et plus particulièrement les structures organisationnelles, les approches pédagogiques, la transition d'un apprentissage axé sur les contenus à un apprentissage axé sur les résultats, les outils modernes de formation et les exigences imposées aux différents prestataires de services de santé animale dans un monde en constante évolution. En conclusion, les auteurs insistent sur l'importance cruciale de mettre en place des dispositifs de formation professionnelle continue destinés au secteur vétérinaire, afin que la qualité des services fournis soit à la hauteur des exigences croissantes et en constante évolution du 21e siècle. Les programmes de FPC doivent donc être conçus en veillant à s'adapter aux besoins des vétérinaires et des professionnels des domaines connexes concernant les compétences spécifiques qu'ils doivent déployer en fonction des exigences de leur activité, qu'ils travaillent auprès des gardiens d'animaux, des professionnels des filières issues de l'élevage, des gouvernements nationaux ou des organismes internationaux chargés de l'élaboration de normes. Un secteur vétérinaire optimisé et performant nécessite un programme de FPC fondé sur des données concrètes afin que les vétérinaires et les autres prestataires de services de santé animale puissent maintenir leur niveau de compétences ainsi que la pertinence de leurs interventions au regard des exigences évolutives d'un monde en pleine transformation. La profession vétérinaire s'est adaptée à maintes reprises et avec succès à de nouveaux défis et évolutions qui ont nécessité la mobilisation d'un grand nombre de compétences nouvelles. La diversité des contextes, des systèmes de production et des exigences sociétales impose à la profession vétérinaire des transformations continues, avec pour conséquences une demande croissante de spécialisation et de collaborations interdisciplinaires le long des chaînes de valeur et la nécessité de mieux se préparer au risque omniprésent de maladies émergentes. Face aux changements intervenus, aux nouvelles connaissances, aux progrès de la recherche et aux nouvelles manières de relever les défis, la formation professionnelle continue (FPC) et l'adaptation et actualisation des cursus d'enseignement vétérinaire ont joué un rôle déterminant pour maintenir et améliorer la qualité et les performances des Services vétérinaires. Les auteurs font le point sur les divers prestataires de services vétérinaires et examinent le rôle essentiel de la FPC pour relever les défis actuels et futurs, en mettant l'accent sur les vétérinaires et les professions connexes travaillant en lien avec les vétérinaires. Ils analysent la contribution des fournisseurs de FPC au système de santé animale, ainsi que l'influence sur la qualité et l'impact du renforcement des capacités d'un certain nombre de facteurs internes et externes à l'échelle des cohortes ou des individus. Les auteurs décrivent également le paysage de la FPC dans le domaine vétérinaire et plus particulièrement les structures organisationnelles, les approches pédagogiques, la transition d'un apprentissage axé sur les contenus à un apprentissage axé sur les résultats, les outils modernes de formation et les exigences imposées aux différents prestataires de services de santé animale dans un monde en constante évolution. En conclusion, les auteurs insistent sur l'importance cruciale de mettre en place des dispositifs de formation professionnelle continue destinés au secteur vétérinaire, afin que la qualité des services fournis soit à la hauteur des exigences croissantes et en constante évolution du 21e siècle. Les programmes de FPC doivent donc être conçus en veillant à s'adapter aux besoins des vétérinaires et des professionnels des domaines connexes concernant les compétences spécifiques qu'ils doivent déployer en fonction des exigences de leur activité, qu'ils travaillent auprès des gardiens d'animaux, des professionnels des filières issues de l'élevage, des gouvernements nationaux ou des organismes internationaux chargés de l'élaboration de normes. Un secteur vétérinaire optimisé et performant nécessite un programme de FPC fondé sur des données concrètes afin que les vétérinaires et les autres prestataires de services de santé animale puissent maintenir leur niveau de compétences ainsi que la pertinence de leurs interventions au regard des exigences évolutives d'un monde en pleine transformation.


La profesión veterinaria siempre ha sabido adaptarse con éxito a las novedades y nuevos problemas que han ido surgiendo, y que requieren la adquisición de nuevos conocimientos y aptitudes. Los diferentes contextos, sistemas productivos y necesidades sociales siguen configurando la profesión veterinaria y generando una creciente demanda de especialización, de colaboración interdisciplinar en todos los eslabones de las cadenas de valor y de preparación ante el omnipresente riesgo que plantean las enfermedades emergentes. El perfeccionamiento profesional continuo (PPC) y la adaptación y actualización de los planes de estudios veterinarios han sido factores esenciales para seguir el ritmo de las transformaciones, las nuevas ideas, los avances científicos y las novedosas respuestas a los problemas y, gracias a ello, mantener y mejorar la calidad y el desempeño de los Servicios Veterinarios. Los autores pasan revista a cuantos agentes intervienen en la prestación de servicios veterinarios y, centrándose en los veterinarios y cuerpos profesionales conexos, exponen la función crucial que cumple el PPC para hacer frente a los problemas de hoy y de mañana. También explican cómo contribuyen al sistema los proveedores de PPC y cómo los factores internos y externos de una cohorte o un individuo afectan a la calidad y la repercusión del desarrollo de capacidades. Además, describen el panorama que ofrece el PPC en veterinaria desde el punto de vista de las estructuras organizativas, los planteamientos pedagógicos, la transición del aprendizaje de asimilación al aprendizaje por resultados, las modernas herramientas de trabajo y las exigencias que deben satisfacer los distintos agentes que intervienen en la prestación de servicios zoosanitarios en un mundo en plena evolución. Los autores concluyen que es de la máxima importancia ocuparse del PPC para que los servicios veterinarios dispensados sigan siendo de calidad y respondiendo a las crecientes y mudables exigencias que trae consigo el siglo XXI. Hay que establecer pues un programa de PPC especialmente adaptado a las necesidades de los veterinarios y cuerpos profesionales conexos, pensando en dotarlos de las competencias necesarias para satisfacer los requisitos propios de su lugar de trabajo, ya obren al servicio de la producción animal, de cadenas de valor ganaderas, de administraciones nacionales o de organismos internacionales de reglamentación. Un sector veterinario optimizado y eficaz requiere un programa de PPC científicamente fundamentado, que sirva a los veterinarios y demás agentes de la prestación de servicios zoosanitarios para seguir siendo a la vez competentes y útiles ante las cambiantes exigencias que les plantea un mundo en plena evolución.


Assuntos
Médicos Veterinários , Animais , Currículo , Humanos
20.
Rev Sci Tech ; 40(2): 469-481, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34542100

RESUMO

Animal welfare is an essential component of the future of sustainable agriculture and the United Nations Sustainable Development Goals. There is growing global recognition of the importance of animal welfare, which must always be considered as part of the decision-making around food and nutrition security. Veterinary Services, encompassing public and private veterinarians and para-veterinarians, are custodians of animal welfare and key players in future actions to improve it. The welfare of animals is everyone's responsibility, from the individual farmer and practitioner to policymakers at the national and intergovernmental level. In this paper, after providing background information about current animal welfare issues and identifying animal welfare risks, the authors make a number of recommendations for action at the institutional and individual level. They do so because while the former is essential to generate change at scale and effective resourcing, the latter can create immediate action at a local level and drive change from the ground up. Without coordinated action from Veterinary Services, opportunities to improve animal welfare, alongside human and environmental health and well-being, may very well be lost, and animal welfare may fail to improve or even be at risk of decline.


L'accélération de la perturbation numérique depuis quelques années est spectaculaire, transformant tous les secteurs de l'économie, y compris la production animale, la santé animale et le bien-être des animaux. Les auteurs s'intéressent à certaines technologies numériques de pointe qui pourraient influencer le devenir des Services vétérinaires. Toutes ces technologies sont orientées données et trouvent leur illustration dans trois exemples qui se répartissent dans les catégories suivantes : a) les technologies sans fil et mobiles appliquées au suivi de la santé animale, à la surveillance des maladies, aux notifications des foyers et à l'échange d'informations ; b) les technologies avancées de traitement des données, dont les mégadonnées et l'analytique de données qui servent à mettre en évidence des structures sous-jacentes, à extraire des schémas prédictifs, à relever des corrélations et à générer d'autres informations ; c) des technologies prometteuses comme les applications « blockchain ¼ (chaînes de blocs) utilisées pour une gestion efficace et efficiente de diverses chaînes d'approvisionnement en intrants. Les auteurs résument brièvement les défis actuels associés au recours accru à ces technologies dans le secteur de la santé animale et en font ressortir certaines répercussions sur les Services vétérinaires. Les technologies numériques vont profondément affecter les modalités de la prestation des services de santé animale ainsi que la gestion des systèmes de santé animale. Par conséquent, il est crucial que les Services vétérinaires anticipent cette évolution et s'adaptent à la transformation numérique en cours. L'investissement dans les nouvelles technologies et les efforts visant à doter les professionnels vétérinaires actuels et futurs des compétences et des connaissances numériques nécessaires pour rester informés et au centre de l'innovation numérique dans le domaine de la santé animale doivent être les priorités des prochaines années.


El bienestar animal es un componente esencial de la agricultura sostenible del futuro y de los Objetivos de Desarrollo Sostenible fijados por las Naciones Unidas. Su importancia está cada vez más clara en todo el mundo. El bienestar de los animales debe ser siempre tenido en cuenta en los procesos decisorios que tocan a la seguridad alimentaria y nutricional. Los Servicios Veterinarios, que comprenden tanto a los veterinarios públicos y privados como al personal paraveterinario, son custodios del bienestar animal y agentes clave de toda acción futura encaminada a mejorarlo. Para lograr que el bienestar animal mejore desde ahora mismo, allí donde haga falta, y asegurar que siga un rumbo de constante progreso en el futuro, es preciso que todos los interlocutores, desde los productores y cuidadores hasta los planificadores de políticas de ámbito nacional e intergubernamental, hagan suya esta responsabilidad. Tras presentar información básica sobre los actuales problemas de bienestar animal y señalar los riesgos existentes en la materia, los autores formulan una serie de recomendaciones para actuar tanto desde las instituciones como a título individual, sabedores de que el primer nivel es fundamental para inducir cambios a gran escala y movilizar recursos eficazmente, mientras que el segundo puede generar inmediatamente acciones a escala local e impulsar desde ahí cambios en sentido ascendente. A falta de una labor coordinada de los Servicios Veterinarios, es muy posible que se pierdan oportunidades para mejorar el bienestar animal, junto con la salud y el bienestar de personas y ecosistemas, y que los niveles de bienestar animal no mejoren o, incluso, corran peligro de deterioro.


Assuntos
Médicos Veterinários , Medicina Veterinária , Agricultura , Bem-Estar do Animal , Animais , Fazendeiros , Humanos
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