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1.
BMC Genomics ; 20(1): 718, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31533632

RESUMO

BACKGROUND: The work of the FANTOM5 Consortium has brought forth a new level of understanding of the regulation of gene transcription and the cellular processes involved in creating diversity of cell types. In this study, we extended the analysis of the FANTOM5 Cap Analysis of Gene Expression (CAGE) transcriptome data to focus on understanding the genetic regulators involved in mouse cerebellar development. RESULTS: We used the HeliScopeCAGE library sequencing on cerebellar samples over 8 embryonic and 4 early postnatal times. This study showcases temporal expression pattern changes during cerebellar development. Through a bioinformatics analysis that focused on transcription factors, their promoters and binding sites, we identified genes that appear as strong candidates for involvement in cerebellar development. We selected several candidate transcriptional regulators for validation experiments including qRT-PCR and shRNA transcript knockdown. We observed marked and reproducible developmental defects in Atf4, Rfx3, and Scrt2 knockdown embryos, which support the role of these genes in cerebellar development. CONCLUSIONS: The successful identification of these novel gene regulators in cerebellar development demonstrates that the FANTOM5 cerebellum time series is a high-quality transcriptome database for functional investigation of gene regulatory networks in cerebellar development.


Assuntos
Cerebelo/crescimento & desenvolvimento , Perfilação da Expressão Gênica , Motivos de Nucleotídeos/genética , Transcrição Genética/genética , Fator 4 Ativador da Transcrição/deficiência , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , Animais , Cerebelo/embriologia , Cerebelo/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Silenciamento de Genes , Camundongos , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas/genética , Fatores de Transcrição de Fator Regulador X/deficiência , Fatores de Transcrição de Fator Regulador X/genética , Fatores de Transcrição de Fator Regulador X/metabolismo , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
2.
Biol Cell ; 111(9): 217-231, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31177551

RESUMO

Ciliopathies are complex genetic multi-system disorders causally related to abnormal assembly or function of motile or non-motile cilia. While most human cells possess a non-motile sensory/primary cilium (PC) during development and/or in adult tissues, motile cilia are restricted to specialised cells. As a result, PC-associated ciliopathies are characterised by high phenotypic variability with extensive clinical and genetic overlaps. In the present review, we have focused on cerebral developmental anomalies, which are commonly found in PC-associated ciliopathies and which have mostly been linked to Hedgehog signalling defects. In addition, we have reviewed emerging evidence that PC dysfunctions could be directly or indirectly involved in the mechanisms underlying malformations of cerebral cortical development including primary microcephaly.


Assuntos
Agenesia do Corpo Caloso/embriologia , Cerebelo/anormalidades , Cílios/patologia , Ciliopatias/embriologia , Hidrocefalia/embriologia , Malformações do Sistema Nervoso/embriologia , Defeitos do Tubo Neural/embriologia , Animais , Cerebelo/embriologia , Deficiências do Desenvolvimento , Proteínas Hedgehog/metabolismo , Humanos , Camundongos , Transdução de Sinais
3.
Nature ; 572(7767): 67-73, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31043743

RESUMO

Study of the origin and development of cerebellar tumours has been hampered by the complexity and heterogeneity of cerebellar cells that change over the course of development. Here we use single-cell transcriptomics to study more than 60,000 cells from the developing mouse cerebellum and show that different molecular subgroups of childhood cerebellar tumours mirror the transcription of cells from distinct, temporally restricted cerebellar lineages. The Sonic Hedgehog medulloblastoma subgroup transcriptionally mirrors the granule cell hierarchy as expected, while group 3 medulloblastoma resembles Nestin+ stem cells, group 4 medulloblastoma resembles unipolar brush cells, and PFA/PFB ependymoma and cerebellar pilocytic astrocytoma resemble the prenatal gliogenic progenitor cells. Furthermore, single-cell transcriptomics of human childhood cerebellar tumours demonstrates that many bulk tumours contain a mixed population of cells with divergent differentiation. Our data highlight cerebellar tumours as a disorder of early brain development and provide a proximate explanation for the peak incidence of cerebellar tumours in early childhood.


Assuntos
Neoplasias Cerebelares/genética , Neoplasias Cerebelares/patologia , Evolução Molecular , Feto/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Regulação Neoplásica da Expressão Gênica , Transcrição Genética , Animais , Neoplasias Cerebelares/classificação , Cerebelo/citologia , Cerebelo/embriologia , Cerebelo/metabolismo , Criança , Feminino , Feto/citologia , Glioma/classificação , Glioma/genética , Glioma/patologia , Humanos , Meduloblastoma/classificação , Meduloblastoma/genética , Meduloblastoma/patologia , Camundongos , Análise de Sequência de RNA , Análise de Célula Única , Fatores de Tempo , Transcriptoma/genética
4.
J Obstet Gynaecol Res ; 45(7): 1245-1250, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30932268

RESUMO

AIM: To explore the effectiveness of cavum septi pellucidi (CSP) width to anteroposterior cerebellar diameter (APCD) ratio as a diagnostic adjunct for prenatal diagnosis of trisomy 18. METHODS: Images of normal fetal brain within 15 and 35 weeks were stored in our center from 2016 to 2017. Images of aneuploid fetuses were retrospectively collected from 2004 to 2017. The transverse cerebellar diameter, APCD and CSP width were measured. CSP/APCD and APCD/transverse cerebellar diameter ratios were calculated and compared between euploid and aneuploid fetuses. RESULTS: One thousand and forty one fetuses were analyzed, including 817 euploid fetuses and 224 aneuploid fetuses (trisomy 21 117 cases, trisomy 18 82 cases, trisomy 13 9 cases, sex-linked 16 cases). No correlation had been found between both ratios and gestational weeks (P > 0.05). In aneuploid groups, means of ratios were both significantly different just between trisomy 18 group and euploid group (P < 0.05). The best area under the curve was shown by the CSP/APCD ratio. The cutoff value of CSP/APCD was 0.46 (sensitivity 87.0%, specificity 85.0%). CONCLUSION: A wide CSP or cerebellar hypoplasia warrants a more detailed ultrasound screening and genetic counseling. A larger CSP/APCD ratio alerts us to trisomy 18 syndrome, especially in cases with subtle anomalies.


Assuntos
Cerebelo/embriologia , Feto/diagnóstico por imagem , Indicadores Básicos de Saúde , Septo Pelúcido/embriologia , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Ultrassonografia Pré-Natal/estatística & dados numéricos , Adulto , Encéfalo/embriologia , Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Deficiências do Desenvolvimento/diagnóstico por imagem , Feminino , Feto/patologia , Idade Gestacional , Humanos , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/embriologia , Gravidez , Valores de Referência , Estudos Retrospectivos , Sensibilidade e Especificidade , Síndrome da Trissomía do Cromossomo 18/embriologia
5.
PLoS One ; 14(2): e0212857, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30794696

RESUMO

Protein SUMOylation regulates multiple processes involved in the differentiation and maturation of cells and tissues during development. Despite this, relatively little is known about the spatial and temporal regulation of proteins that mediate SUMOylation and deSUMOylation in the CNS. Here we monitor the expression of key SUMO pathway proteins and levels of substrate protein SUMOylation in the forebrain and cerebellum of Wistar rats during development. Overall, the SUMOylation machinery is more highly-expressed at E18 and decreases thereafter, as previously described. All of the proteins investigated are less abundant in adult than in embryonic brain. Furthermore, we show for first time that the profiles differ between cerebellum and cerebrum, indicating differential regional regulation of some of the proteins analysed. These data provide further basic observation that may open a new perspective of research about the role of SUMOylation in the development of different brain regions.


Assuntos
Cerebelo/embriologia , Cérebro/embriologia , Proteínas do Tecido Nervoso/metabolismo , Sumoilação/fisiologia , Animais , Cerebelo/citologia , Cérebro/citologia , Ratos , Ratos Wistar
6.
Neuron ; 101(4): 707-720.e5, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30638744

RESUMO

RNA-binding proteins (RBPs) regulate genetic diversity, but the degree to which they do so in individual cell types in vivo is unknown. We developed NOVA2 cTag-crosslinking and immunoprecipitation (CLIP) to generate functional RBP-RNA maps from different neuronal populations in the mouse brain. Combining cell type datasets from Nova2-cTag and Nova2 conditional knockout mice revealed differential NOVA2 regulatory actions on alternative splicing (AS) on the same transcripts expressed in different neurons. This includes functional differences in transcripts expressed in cortical and cerebellar excitatory versus inhibitory neurons, where we find NOVA2 is required for, respectively, development of laminar structure, motor coordination, and synapse formation. We also find that NOVA2-regulated AS is coupled to NOVA2 regulation of intron retention in hundreds of transcripts, which can sequester the trans-acting splicing factor PTBP2. In summary, cTag-CLIP complements single-cell RNA sequencing (RNA-seq) studies by providing a means for understanding RNA regulation of functional cell diversity.


Assuntos
Processamento Alternativo , Antígenos de Neoplasias/genética , Cerebelo/embriologia , Córtex Cerebral/embriologia , Neurogênese , Neurônios/metabolismo , Proteínas de Ligação a RNA/genética , Animais , Antígenos de Neoplasias/metabolismo , Células Cultivadas , Cerebelo/citologia , Cerebelo/fisiologia , Córtex Cerebral/citologia , Potenciais Pós-Sinápticos Excitadores , Feminino , Potenciais Pós-Sinápticos Inibidores , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/citologia , Neurônios/fisiologia , Proteína de Ligação a Regiões Ricas em Polipirimidinas/genética , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , Proteínas de Ligação a RNA/metabolismo
7.
Dev Biol ; 448(1): 36-47, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30695685

RESUMO

Joubert syndrome (JBTS) is a predominantly autosomal recessive neurodevelopmental disorder that presents with characteristic malformations of the cerebellar vermis, superior cerebellar peduncles and midbrain in humans. Accompanying these malformations are a heterogeneous set of clinical symptoms, which frequently include deficits in motor and muscle function, such as hypotonia (low muscle tone) and ataxia (clumsiness). These symptoms are attributed to improper development of the hindbrain, but no direct evidence has been reported linking these in JBTS. Here, we describe muscle developmental defects in a mouse with a targeted deletion of the Abelson helper integration site 1 gene, Ahi1, one of the genes known to cause JBTS in humans. While FVB/NJ Ahi1-/- mice display no gross malformations of the cerebellum, deficits are observed in several measures of motor function, strength, and body development. Specifically, Ahi1-/- mice show delayed physical development, delays in surface reflex righting as neonates, and reductions in grip strength and spontaneous locomotor activity as adults. Additionally, Ahi1-/- mice showed evidence of muscle-specific contributions to this phenotype, such as reductions in 1) myoblast differentiation potential in vitro, 2) muscle desmin expression, and 3) overall muscle mass, myonuclear domain, and muscle fiber cross-sectional area. Together, these data suggest that loss of Ahi1 may cause abnormalities in the differentiation of myoblasts to mature muscle cells. Moreover, Ahi1 loss impacts muscle development directly, outside of any indirect impact of cerebellar malformations, revealing a novel myogenic cause for hypotonia in JBTS.


Assuntos
Anormalidades Múltiplas/embriologia , Diferenciação Celular , Cerebelo/anormalidades , Anormalidades do Olho/embriologia , Doenças Renais Císticas/embriologia , Desenvolvimento Muscular , Transtornos do Neurodesenvolvimento/metabolismo , Proteínas Proto-Oncogênicas/deficiência , Retina/anormalidades , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Proteínas Adaptadoras de Transporte Vesicular , Animais , Cerebelo/embriologia , Cerebelo/patologia , Desmina/genética , Desmina/metabolismo , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Locomoção/genética , Camundongos , Camundongos Knockout , Força Muscular/genética , Mioblastos/metabolismo , Mioblastos/patologia , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Proteínas Proto-Oncogênicas/metabolismo , Reflexo de Endireitamento/genética , Retina/embriologia , Retina/patologia
8.
Int J Mol Sci ; 19(12)2018 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-30545052

RESUMO

Caspase-3, onto which there is a convergence of the intrinsic and extrinsic apoptotic pathways, is the main executioner of apoptosis. We here review the current literature on the intervention of the protease in the execution of naturally occurring neuronal death (NOND) during cerebellar development. We will consider data on the most common altricial species (rat, mouse and rabbit), as well as humans. Among the different types of neurons and glia in cerebellum, there is ample evidence for an intervention of caspase-3 in the regulation of NOND of the post-mitotic cerebellar granule cells (CGCs) and Purkinje neurons, as a consequence of failure to establish proper synaptic contacts with target (secondary cell death). It seems possible that the GABAergic interneurons also undergo a similar type of secondary cell death, but the intervention of caspase-3 in this case still remains to be clarified in full. Remarkably, CGCs also undergo primary cell death at the precursor/pre-migratory stage of differentiation, in this instance without the intervention of caspase-3. Glial cells, as well, undergo a process of regulated cell death, but it seems possible that expression of caspase-3, at least in the Bergmann glia, is related to differentiation rather than death.


Assuntos
Caspase 3/metabolismo , Cerebelo/citologia , Cerebelo/embriologia , Mamíferos/embriologia , Animais , Morte Celular , Neurônios/citologia
9.
Prenat Diagn ; 38(13): 1042-1048, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30328635

RESUMO

OBJECTIVE: Anomalous neurological development associated with congenital heart disease (CHD) has been reported as early as third trimester of fetal development. While several studies have characterized variations in CHD neurodevelopmental outcomes in early childhood, these reports are often confounded by postnatal factors such as surgical outcome. Recent studies have focused on the comparing neurological variations between fetuses with CHD and normal controls. In this work, we present a comparison of in utero variations in brain development between fetuses with different types of CHD, by analyzing them under categories of single ventricle versus biventricular cardiac anatomy. METHODS: Using recent advances in fetal magnetic resonance imaging (MRI), we quantify the volumetric trajectories of various brain tissues (such as cortical plate, developing white matter, cerebrospinal fluid [CSF], and cerebellum). RESULTS: Our study is the first to differentiate between intraventricular and extra-axial CSF thereby allowing us to better identify variations in brain composition of the fetuses. CONCLUSIONS: Overall, our findings show that while total brain volume is similar between fetuses with single and biventricular anatomy, they exhibit statistically significant disparity in brain composition.


Assuntos
Encéfalo/diagnóstico por imagem , Feto/diagnóstico por imagem , Cardiopatias Congênitas/diagnóstico por imagem , Encéfalo/anormalidades , Encéfalo/embriologia , Estudos de Casos e Controles , Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Cerebelo/embriologia , Córtex Cerebral/anormalidades , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/embriologia , Circulação Cerebrovascular , Dupla Via de Saída do Ventrículo Direito/complicações , Dupla Via de Saída do Ventrículo Direito/diagnóstico por imagem , Dupla Via de Saída do Ventrículo Direito/fisiopatologia , Anomalia de Ebstein/diagnóstico por imagem , Anomalia de Ebstein/fisiopatologia , Ecocardiografia , Feminino , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/fisiopatologia , Humanos , Síndrome do Coração Esquerdo Hipoplásico/complicações , Síndrome do Coração Esquerdo Hipoplásico/diagnóstico por imagem , Síndrome do Coração Esquerdo Hipoplásico/fisiopatologia , Imagem por Ressonância Magnética , Circulação Placentária , Gravidez , Segundo Trimestre da Gravidez , Terceiro Trimestre da Gravidez , Ultrassonografia Doppler , Ultrassonografia Pré-Natal , Substância Branca/anormalidades , Substância Branca/diagnóstico por imagem , Substância Branca/embriologia
10.
Elife ; 72018 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-30311906

RESUMO

Proper brain development relies highly on protein N-glycosylation to sustain neuronal migration, axon guidance and synaptic physiology. Impairing the N-glycosylation pathway at early steps produces broad neurological symptoms identified in congenital disorders of glycosylation. However, little is known about the molecular mechanisms underlying these defects. We generated a cerebellum specific knockout mouse for Srd5a3, a gene involved in the initiation of N-glycosylation. In addition to motor coordination defects and abnormal granule cell development, Srd5a3 deletion causes mild N-glycosylation impairment without significantly altering ER homeostasis. Using proteomic approaches, we identified that Srd5a3 loss affects a subset of glycoproteins with high N-glycans multiplicity per protein and decreased protein abundance or N-glycosylation level. As IgSF-CAM adhesion proteins are critical for neuron adhesion and highly N-glycosylated, we observed impaired IgSF-CAM-mediated neurite outgrowth and axon guidance in Srd5a3 mutant cerebellum. Our results link high N-glycan multiplicity to fine-tuned neural cell adhesion during mammalian brain development.


Assuntos
Cerebelo/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Polissacarídeos/metabolismo , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/deficiência , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo , Animais , Orientação de Axônios , Adesão Celular , Moléculas de Adesão Celular/metabolismo , Diferenciação Celular , Membrana Celular/metabolismo , Cerebelo/embriologia , Grânulos Citoplasmáticos/metabolismo , Deleção de Genes , Glicosilação , Imunoglobulinas/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Proteínas de Membrana/deficiência , Proteínas de Membrana/metabolismo , Camundongos Knockout , Atividade Motora , Mutação/genética , Vias Neurais/metabolismo , Proteômica , Células de Purkinje/metabolismo , Reprodutibilidade dos Testes , Resposta a Proteínas não Dobradas
11.
Curr Biol ; 28(18): 2910-2920.e2, 2018 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-30220501

RESUMO

The cerebellum develops from a restricted number of cell types that precisely organize to form the circuitry that controls sensory-motor coordination and some higher-order cognitive processes. To acquire an enhanced understanding of the molecular processes that mediate cerebellar development, we performed single-cell RNA-sequencing of 39,245 murine cerebellar cells at twelve critical developmental time points. Using recognized lineage markers, we confirmed that the single-cell data accurately recapitulate cerebellar development. We then followed distinct populations from emergence through migration and differentiation, and determined the associated transcriptional cascades. After identifying key lineage commitment decisions, focused analyses uncovered waves of transcription factor expression at those branching points. Finally, we created Cell Seek, a flexible online interface that facilitates exploration of the dataset. Our study provides a transcriptional summarization of cerebellar development at single-cell resolution that will serve as a valuable resource for future investigations of cerebellar development, neurobiology, and disease.


Assuntos
Diferenciação Celular , Movimento Celular , Neurogênese , Transcriptoma , Animais , Cerebelo/citologia , Cerebelo/embriologia , Embrião de Mamíferos , Desenvolvimento Embrionário , Feminino , Camundongos , Camundongos Endogâmicos ICR , Análise de Célula Única
12.
PLoS Biol ; 16(9): e2005513, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30260948

RESUMO

The morphological, molecular, and functional heterogeneity of astrocytes is under intense scrutiny, but how this diversity is ontogenetically achieved remains largely unknown. Here, by quantitative in vivo clonal analyses and proliferation studies, we demonstrate that the major cerebellar astrocyte types emerge according to an unprecedented and remarkably orderly developmental program comprising (i) a time-dependent decline in both clone size and progenitor multipotency, associated with clone allocation first to the hemispheres and then to the vermis(ii) distinctive clonal relationships among astrocyte types, revealing diverse lineage potentials of embryonic and postnatal progenitors; and (iii) stereotyped clone architectures and recurrent modularities that correlate to layer-specific dynamics of postnatal proliferation/differentiation. In silico simulations indicate that the sole presence of a unique multipotent progenitor at the source of the whole astrogliogenic program is unlikely and rather suggest the involvement of additional committed components.


Assuntos
Astrócitos/citologia , Cerebelo/citologia , Animais , Animais Recém-Nascidos , Ciclo Celular , Diferenciação Celular , Linhagem da Célula , Proliferação de Células , Tamanho Celular , Cerebelo/embriologia , Células Clonais , Simulação por Computador , Feminino , Humanos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Substância Branca/citologia
13.
Dev Psychopathol ; 30(3): 743-762, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30068407

RESUMO

The prenatal period is increasingly considered as a crucial target for the primary prevention of neurodevelopmental and psychiatric disorders. Understanding their pathophysiological mechanisms remains a great challenge. Our review reveals new insights from prenatal brain development research, involving (epi)genetic research, neuroscience, recent imaging techniques, physical modeling, and computational simulation studies. Studies examining the effect of prenatal exposure to maternal distress on offspring brain development, using brain imaging techniques, reveal effects at birth and up into adulthood. Structural and functional changes are observed in several brain regions including the prefrontal, parietal, and temporal lobes, as well as the cerebellum, hippocampus, and amygdala. Furthermore, alterations are seen in functional connectivity of amygdalar-thalamus networks and in intrinsic brain networks, including default mode and attentional networks. The observed changes underlie offspring behavioral, cognitive, emotional development, and susceptibility to neurodevelopmental and psychiatric disorders. It is concluded that used brain measures have not yet been validated with regard to sensitivity, specificity, accuracy, or robustness in predicting neurodevelopmental and psychiatric disorders. Therefore, more prospective long-term longitudinal follow-up studies starting early in pregnancy should be carried out, in order to examine brain developmental measures as mediators in mediating the link between prenatal stress and offspring behavioral, cognitive, and emotional problems and susceptibility for disorders.


Assuntos
Encéfalo/embriologia , Encéfalo/fisiopatologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Estresse Psicológico/complicações , Tonsila do Cerebelo/embriologia , Tonsila do Cerebelo/fisiopatologia , Cerebelo/embriologia , Cerebelo/fisiopatologia , Feminino , Hipocampo/embriologia , Hipocampo/fisiopatologia , Humanos , Lactente , Recém-Nascido , Masculino , Rede Nervosa/embriologia , Rede Nervosa/fisiopatologia , Transtornos do Neurodesenvolvimento/psicologia , Lobo Parietal/embriologia , Lobo Parietal/fisiopatologia , Córtex Pré-Frontal/embriologia , Córtex Pré-Frontal/fisiopatologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/psicologia , Estudos Prospectivos , Fatores de Risco , Lobo Temporal/embriologia , Lobo Temporal/fisiopatologia
14.
Top Magn Reson Imaging ; 27(4): 275-302, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30086112

RESUMO

: The cerebellum has long been recognized as a fundamental structure in motor coordination. Structural cerebellar abnormalities and diseases involving the cerebellum are relatively common in children. The not always specific clinical presentation of ataxia, incoordination, and balance impairment can often be a challenge to attain a precise diagnosis. Continuous advances in genetic research and moreover the constant development in neuroimaging modalities, particularly in the field of magnetic resonance imaging, have promoted a better understanding of cerebellar diseases and led to several modifications in their classification in recent years. Thorough clinical and neuroimaging investigation is recommended for proper diagnosis. This review outlines an update of causes of cerebellar disorders that present clinically with ataxia in the pediatric population. These conditions were classified in 2 major groups, namely genetic malformations and acquired or disruptive disorders recognizable by neuroimaging and subsequently according to their features during the prenatal and postnatal periods.


Assuntos
Ataxia Cerebelar/diagnóstico por imagem , Cerebelo/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Neuroimagem/métodos , Diagnóstico Pré-Natal/métodos , Adolescente , Ataxia Cerebelar/patologia , Cerebelo/embriologia , Cerebelo/patologia , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Masculino , Gravidez
16.
F1000Res ; 72018.
Artigo em Inglês | MEDLINE | ID: mdl-30109024

RESUMO

The cerebellum is the focus of an emergent series of debates because its circuitry is now thought to encode an unexpected level of functional diversity. The flexibility that is built into the cerebellar circuit allows it to participate not only in motor behaviors involving coordination, learning, and balance but also in non-motor behaviors such as cognition, emotion, and spatial navigation. In accordance with the cerebellum's diverse functional roles, when these circuits are altered because of disease or injury, the behavioral outcomes range from neurological conditions such as ataxia, dystonia, and tremor to neuropsychiatric conditions, including autism spectrum disorders, schizophrenia, and attention-deficit/hyperactivity disorder. Two major questions arise: what types of cells mediate these normal and abnormal processes, and how might they accomplish these seemingly disparate functions? The tiny but numerous cerebellar granule cells may hold answers to these questions. Here, we discuss recent advances in understanding how the granule cell lineage arises in the embryo and how a stem cell niche that replenishes granule cells influences wiring when the postnatal cerebellum is injured. We discuss how precisely coordinated developmental programs, gene expression patterns, and epigenetic mechanisms determine the formation of synapses that integrate multi-modal inputs onto single granule cells. These data lead us to consider how granule cell synaptic heterogeneity promotes sensorimotor and non-sensorimotor signals in behaving animals. We discuss evidence that granule cells use ultrafast neurotransmission that can operate at kilohertz frequencies. Together, these data inspire an emerging view for how granule cells contribute to the shaping of complex animal behaviors.


Assuntos
Cerebelo/citologia , Neurônios/citologia , Animais , Cerebelo/embriologia , Desenvolvimento Embrionário , Humanos , Córtex Sensório-Motor/citologia
17.
J Comp Neurol ; 526(14): 2187-2203, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29888788

RESUMO

The majority of neurons in the mammalian brain reside within the cerebellum (Cb). Yet, the evolutionary origins of the Cb are not well understood. There are several sensory nuclei present across vertebrate phylogeny collectively termed cerebellum-like structures (CbLS) due to a shared anatomy and physiology with the Cb. Despite the similarities, the CbLS are clearly not phylogenetically homologous with the Cb. Common structure and function may arise due to a shared genetic and developmental toolkit. To examine this possibility, we used sequence analysis, western blotting, immunohistochemistry and RT-qPCR to test for the expression of three genes that are critical for mammalian cerebellar development in the Cb and CbLS of an elasmobranch fish, Leucoraja erinacea. In the mammalian Cb, Pax6 is necessary for parallel fiber development, while Cbln1 and Grid2 code for proteins necessary for parallel fiber-principal cell synaptogenesis. Pax6 and Cbln1 are expressed by granule cells in the Cb and CbLS of the adult skate and stage 31 embryo. Grid2 is expressed by principal cells in the Cb and CbLS of the adult and stage 31 embryo. RT-qPCR showed this expression is spatially and temporally restricted to the Cb and CbLS. If Pax6, Cbln1 and Grid2 perform the same functions in the skate Cb and CbLS as they do in the mammalian Cb, then these structures may develop using a shared genetic toolkit and be considered generatively homologous. It is possible that the evolutionary genesis of the Cb was the result of duplication or expansion of the cerebellum-like developmental toolkit.


Assuntos
Cerebelo/anatomia & histologia , Cerebelo/metabolismo , Proteínas do Tecido Nervoso/genética , Fator de Transcrição PAX6/genética , Receptores de Glutamato/genética , /anatomia & histologia , Animais , Sequência de Bases , Cerebelo/embriologia , Grânulos Citoplasmáticos/metabolismo , DNA Complementar/biossíntese , DNA Complementar/genética , Embrião não Mamífero , Duplicação Gênica , Regulação da Expressão Gênica , Imuno-Histoquímica , Homologia de Sequência do Ácido Nucleico
18.
Handb Clin Neurol ; 154: 219-234, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29903441

RESUMO

Conventional magnetic resonance imaging (MRI) allows for a detailed noninvasive visualization/examination of posterior fossa structures and represents a fundamental step in the diagnostic workup of many cerebellar disorders. In the first part of this chapter methodologic issues, like the correct choice of hardware (magnets, coils), pro and cons of the different MRI sequences, and patient management during the examination are discussed. In the second part, the MRI anatomy of the cerebellum, as noted on the various conventional MRI sequences, as well as a detailed description of cerebellar maturational processes from birth to childhood and into adulthood, are reported. Volumetric studies on the cerebellar growth based on three-dimensional MRI sequences are also presented. Moreover, we briefly discuss two main topics regarding conventional MRI of the cerebellum that have generated some debate in recent years: the differentiation between cerebellar atrophy, hypoplasia, and pontocerebellar hypoplasia, and signal changes of dentate nuclei after repetitive gadolinium-based contrast injections. The advantages and benefits of advanced neuroimaging techniques, including 1H magnetic resonance spectroscopy, diffusion-weighted imaging, diffusion tensor imaging, and perfusion-weighted imaging are discussed in the last section of the chapter.


Assuntos
Doenças Cerebelares/diagnóstico por imagem , Cerebelo/diagnóstico por imagem , Imagem por Ressonância Magnética , Fatores Etários , Cerebelo/anatomia & histologia , Cerebelo/embriologia , Cerebelo/crescimento & desenvolvimento , Humanos , Processamento de Imagem Assistida por Computador
19.
Handb Clin Neurol ; 154: 29-44, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29903446

RESUMO

With the growing recognition of the extent and prevalence of human cerebellar disorders, an understanding of developmental programs that build the mature cerebellum is necessary. In this chapter we present an overview of the basic epochs and key molecular regulators of the developmental programs of cerebellar development. These include early patterning of the cerebellar territory, the genesis of cerebellar cells from multiple spatially distinct germinal zones, and the extensive migration and coordinated cellular rearrangements that result in the formation of the exquisitely foliated and laminated mature cerebellum. This knowledge base is founded on extensive analysis of animal models, particularly mice, due in large part to the ease of genetic manipulation of this important model organism. Since cerebellar structure and function are largely conserved across species, mouse cerebellar development is highly relevant to humans and has led to important insights into the developmental pathogenesis of human cerebellar disorders. Human fetal cerebellar development remains largely undescribed; however, several human-specific developmental features are known which are relevant to human disease and underline the importance of ongoing human fetal research.


Assuntos
Cerebelo , Embriologia , Neurônios/fisiologia , Animais , Cerebelo/citologia , Cerebelo/embriologia , Cerebelo/crescimento & desenvolvimento , Humanos
20.
Handb Clin Neurol ; 154: 3-26, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29903448

RESUMO

This chapter is concerned with ideas on the function, structure, and pathology that shaped our present knowledge of the cerebellum. One of the main themes in its early history is its localization subtentorially, leading to misattributions due to clinical observations in trauma and lesion experiments that caused collateral damage to the brainstem. Improvement of techniques led to the insight that it plays a role in movement control (Rolando) or coordination (Flourens). Purkinje initiated the histology of the cerebellar cortex in 1837. Luciani's experiments in 1891 led him to conclude that the cerebellum has a tonic facilitating effect on central structures. Cajal identified the elements of the cortex and their circuitry (1888-1891). The inhibitory nature of the interneurons and the Purkinje cells, and the excitatory connections of the mossy and climbing afferents and the granule cells were established much later by Eccles and Ito. A functional localization for the coordinating action of the cerebellum of the motor system, based on local expansion of the folial chains, was devised by Bolk in 1906. Babinski and Holmes contributed to anatomoclinical insights. Magnus and coworkers showed the cerebellum does not play an essential role in body posture. The heterogeneity of the Purkinje cells with respect to their connections and histochemistry found its expression in the zonal organization of the cerebellar cortex. The roots of modern developments, like cerebellar learning and its involvement in cognition and emotion, can be traced to the theories of Marr and Albus and the pioneering work of the Leiners and Dow.


Assuntos
Anatomia/história , Pesquisa Biomédica/história , Cerebelo , Ilustração Médica/história , Animais , Pesquisa Biomédica/métodos , Cerebelo/anatomia & histologia , Cerebelo/embriologia , Cerebelo/fisiologia , História do Século XVIII , História do Século XIX , História do Século XX , Humanos , Neurônios/fisiologia
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