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1.
Cell Prolif ; 52(3): e12608, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30932251

RESUMO

OBJECTIVES: We performed histological, cellular and behavioural analyses of the effects of cyclophosphamide (CTX), a chemotherapeutic drug, in the developing cerebellum and aimed to provide valuable insights into clinical application of CTX in children. MATERIALS AND METHODS: C57BL/6 mice and Math1-dependent GFP expression transgenic mice were used in the research. H&E staining was performed to analyse histological effects of CTX in the cerebellum. Staining for EdU and TUNEL was used to estimate the cell proliferation and apoptosis. Rotarod test and hanging wire test were used to evaluate the behavioural functions. Immunofluorescent staining was used to identify the cell types. The differentiation markers and genes related to Sonic Hedgehog (SHH) signalling were measured via quantitative real-time PCR or immunoblotting. RESULTS: We found that while CTX induced a significant reduction in cell proliferation and increased apoptosis in the EGL in 48 hours, the behavioural functions and the multilayer laminar structure of cerebella were largely restored when the mice grew to adults. Mechanistically, granule neuron progenitors, driven by the SHH signalling, enhanced the capability of proliferation quickly after CTX administration was stopped, which allowed the developing cerebellum to catch up and to gradually replenish the injury. CONCLUSION: The chemotherapeutic agent CTX induces an immediate damage to the developing cerebellum, but the cerebellar multilayer laminar structure and motor function can be largely restored if the agent is stopped shortly after use.


Assuntos
Antineoplásicos Alquilantes/efeitos adversos , Comportamento Animal/efeitos dos fármacos , Cerebelo/efeitos dos fármacos , Ciclofosfamida/efeitos adversos , Animais , Animais Recém-Nascidos , Antineoplásicos Alquilantes/administração & dosagem , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cerebelo/crescimento & desenvolvimento , Cerebelo/patologia , Criança , Ciclofosfamida/administração & dosagem , Proteínas Hedgehog/metabolismo , Humanos , Injeções Intraperitoneais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Animais , Neurogênese/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
2.
Artigo em Inglês | MEDLINE | ID: mdl-30893812

RESUMO

Osteopontin (OPN) is a multi-functional protein that binds to integrin and calcium-binding phosphoprotein. OPN is required for normal neuronal development and its axonal myelination. We studied the combined effect of lead (Pb) and ascorbic acid treatment on OPN expression in the developing cerebellum. We randomly divided pregnant female rats into three groups: control, Pb (lead acetate, 0.3%, drinking water), and Pb plus ascorbic acid (PA; ascorbic acid, 100 mg/kg, oral intubation) groups. The blood level of Pb was significantly increased, while ascorbic acid reduced Pb levels in the dams and pups. At postnatal day (PND) 21, results from Nissl staining and OPN immunohistochemistry demonstrated that OPN was detected in the Purkinje cell layer in the cerebellum. Ascorbic acid treatment mitigated Pb exposure-induced reduction in the number of intact Purkinje cells and OPN immunoreactive Purkinje cells in the cerebellum of pups. In addition, Pb-induced reduction in the number of oligodendrocytes and myelin-associated glycoprotein is associated with the malformation of the myelin sheath. Ascorbic acid provided protection from Pb-induced impairments. Pb-induced structural deficits in the cerebellum resulted in functional deterioration observed during locomotive tests (bar holding test and wire mesh ascending test), while ascorbic acid ameliorated these harmful effects. Present results suggest that the change of OPN is associated with myelination in the developing cerebellum. The results also demonstrated that exposure to Pb is harmful, while ascorbic acid treatment is beneficial.


Assuntos
Ácido Ascórbico/farmacologia , Cerebelo/efeitos dos fármacos , Cerebelo/crescimento & desenvolvimento , Chumbo/toxicidade , Osteopontina/metabolismo , Animais , Axônios/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Masculino , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Osteopontina/genética , Gravidez , Distribuição Aleatória , Ratos
3.
Brain Struct Funct ; 224(3): 1359-1375, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30729998

RESUMO

Sensorimotor function is a fundamental brain function in humans, and the cerebrocerebellar circuit is essential to this function. In this study, we demonstrate how the cerebrocerebellar circuit develops both functionally and anatomically from childhood to adulthood in the typically developing human brain. We measured brain activity using functional magnetic resonance imaging while a total of 57 right-handed, blindfolded, healthy children (aged 8-11 years), adolescents (aged 12-15 years), and young adults (aged 18-23 years) (n = 19 per group) performed alternating extension-flexion movements of their right wrists in precise synchronization with 1-Hz audio tones. We also collected their diffusion MR images to examine the extent of fiber maturity in cerebrocerebellar afferent and efferent tracts by evaluating the anisotropy-sensitive index of hindrance modulated orientational anisotropy (HMOA). During the motor task, although the ipsilateral cerebellum and the contralateral primary sensorimotor cortices were consistently activated across all age groups, the functional connectivity between these two distant regions was stronger in adults than in children and adolescents, whereas connectivity within the local cerebellum was stronger in children and adolescents than in adults. The HMOA values in cerebrocerebellar afferent and efferent tracts were higher in adults than in children (some were also higher than in adolescents). The results indicate that adult-like cerebrocerebellar functional coupling is not completely achieved during childhood and adolescence, even for fundamental sensorimotor brain function, probably due to anatomical immaturity of cerebrocerebellar tracts. This study clearly demonstrated the principle of "local-to-distant" development of functional brain networks in the human cerebrocerebellar sensorimotor network.


Assuntos
Cerebelo/diagnóstico por imagem , Cerebelo/crescimento & desenvolvimento , Imagem de Difusão por Ressonância Magnética , Imagem por Ressonância Magnética , Vias Neurais/diagnóstico por imagem , Vias Neurais/crescimento & desenvolvimento , Adolescente , Fatores Etários , Mapeamento Encefálico , Criança , Feminino , Lateralidade Funcional , Mãos/inervação , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Movimento , Rede Nervosa/diagnóstico por imagem , Oxigênio/sangue , Punho/inervação , Adulto Jovem
4.
Brain Dev ; 41(6): 490-500, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30770148

RESUMO

AIM: To clarify the morphologic characteristics of the brain, which are the foundation of the emergence of general movements (GMs) in very-low-birth-weight infants. STUDY DESIGN: Prospective cohort study. GMs were scored according to a semiquantitative scoring system: the GMs optimality score (GMOS) at preterm and term ages. Brain magnetic resonance imaging (MRI) at term-equivalent age was scored using a validated scoring system (MRI score). We examined the relationship between the two scores by multiple regression analysis with relevant clinical background. SUBJECTS: We included 50 very-low-birth-weight infants cared for at Oita University Hospital from August 2012 to August 2018 who underwent MRI and GMs assessment. Their median gestational age and birth weight were 29w2d and 1145 g, respectively. RESULTS: The MRI score and systemic steroid administration were related to preterm GMOS, and the MRI score was related to term GMOS. The component cerebellum score and cortical grey matter score of the MRI score were associated with preterm GMOS, and the cerebellum and the cerebral white matter scores were associated with term GMOS. CONCLUSION: The quality of GMs was associated with brain morphological development. The co-evaluation of GMs and brain morphology leads to accurate developmental prediction.


Assuntos
Encéfalo/patologia , Recém-Nascido Prematuro/crescimento & desenvolvimento , Movimento/fisiologia , Encéfalo/crescimento & desenvolvimento , Cerebelo/crescimento & desenvolvimento , Cerebelo/patologia , Desenvolvimento Infantil , Estudos de Coortes , Feminino , Idade Gestacional , Substância Cinzenta/crescimento & desenvolvimento , Substância Cinzenta/patologia , Humanos , Lactente , Recém-Nascido , Recém-Nascido de muito Baixo Peso/fisiologia , Japão , Imagem por Ressonância Magnética/métodos , Masculino , Triagem Neonatal/métodos , Estudos Prospectivos , Substância Branca/crescimento & desenvolvimento , Substância Branca/patologia
5.
Soft Matter ; 15(10): 2204-2215, 2019 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-30758032

RESUMO

The cerebellum is a tightly folded structure located at the back of the head. Unlike the folds of the cerebrum, the folds of the cerebellum are aligned such that the external surface appears to be covered in parallel grooves. Experiments have shown that anchoring center initiation drives cerebellar foliation. However, the mechanism guiding the location of these anchoring centers, and subsequently cerebellar morphology, remains poorly understood. In particular, there is no definitive mechanistic explanation for the preferential emergence of parallel folds instead of an irregular folding pattern like in the cerebral cortex. Here we use mechanical modeling on the cellular and tissue scales to show that the oriented granule cell division observed in the experimental setting leads to the characteristic parallel folding pattern of the cerebellum. Specifically, we propose an agent-based model of cell clones, a strategy for propagating information from our in silico cell clones to the tissue scale, and an analytical solution backed by numerical results to understand how differential growth between the cerebellar layers drives geometric instability in three dimensional space on the tissue scale. This proposed mechanical model provides further insight into the process of anchoring center initiation and establishes a framework for future multiscale mechanical analysis of developing organs.


Assuntos
Divisão Celular , Cerebelo/citologia , Cerebelo/crescimento & desenvolvimento , Fenômenos Mecânicos , Morfogênese , Fenômenos Biomecânicos , Modelos Biológicos , Neurônios/citologia
6.
Neurosci Lett ; 688: 2-13, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29746896

RESUMO

The cerebellum has a well-established role in controlling motor functions such coordination, balance, posture, and skilled learning. There is mounting evidence that it might also play a critical role in non-motor functions such as cognition and emotion. It is therefore not surprising that cerebellar defects are associated with a wide array of diseases including ataxia, dystonia, tremor, schizophrenia, dyslexia, and autism spectrum disorder. What is intriguing is that a seemingly uniform circuit that is often described as being "simple" should carry out all of these behaviors. Analyses of how cerebellar circuits develop have revealed that such descriptions massively underestimate the complexity of the cerebellum. The cerebellum is in fact highly patterned and organized around a series of parasagittal stripes and transverse zones. This topographic architecture partitions all cerebellar circuits into functional modules that are thought to enhance processing power during cerebellar dependent behaviors. What are arguably the most remarkable features of cerebellar topography are the developmental processes that produce them. This review is concerned with the genetic and cellular mechanisms that orchestrate cerebellar patterning. We place a major focus on how Purkinje cells control multiple aspects of cerebellar circuit assembly. Using this model, we discuss evidence for how "zebra-like" patterns in Purkinje cells sculpt the cerebellum, how specific genetic cues mediate the process, and how activity refines the patterns into an adult map that is capable of executing various functions. We also discuss how defective Purkinje cell patterning might impact the pathogenesis of neurological conditions.


Assuntos
Doenças Cerebelares/fisiopatologia , Cerebelo/crescimento & desenvolvimento , Cerebelo/fisiologia , Células de Purkinje/fisiologia , Animais , Doenças Cerebelares/patologia , Cerebelo/anatomia & histologia , Cerebelo/patologia , Humanos , Células de Purkinje/patologia
7.
Neurosci Lett ; 688: 58-61, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29421544

RESUMO

A puzzling observation in the study of autism spectrum disorder (ASD) in mouse models has been the deregulation of long-term synaptic depression (LTD), a form of experience-dependent synaptic plasticity, across brain areas and across syndromic and non-syndromic forms of autism. This review attempts to approach this phenomenon from a largely, but not exclusively, cerebellar perspective. Three potential consequences of LTD deregulation are discussed that are relevant for ASD phenotypes: resulting impairment of proper developmental synaptic pruning, impairment of motor coordination and motor learning, and impairment of the processing of sensory input.


Assuntos
Transtorno do Espectro Autista/fisiopatologia , Cerebelo/fisiopatologia , Depressão Sináptica de Longo Prazo/fisiologia , Plasticidade Neuronal/fisiologia , Animais , Cerebelo/crescimento & desenvolvimento , Humanos
8.
Neurosci Lett ; 688: 14-25, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29802918

RESUMO

Structural birth defects of the cerebellum, or cerebellar malformations, in humans, have long been recognized. However, until recently there has been little progress in elucidating their developmental pathogenesis. Innovations in brain imaging and human genetic technologies over the last 2 decades have led to better classifications of these disorders and identification of several causative genes. In contrast, cerebellar malformations in model organisms, particularly mice, have been the focus of intense study for more than 70 years. As a result, many of the molecular, genetic and cellular programs that drive formation of the cerebellum have been delineated in mice. In this review, we overview the basic epochs and key molecular regulators of the developmental programs that build the structure of the mouse cerebellum. This mouse-centric approach has been a useful to interpret the developmental pathogenesis of human cerebellar malformations. However, it is becoming apparent that we actually know very little regarding the specifics of human cerebellar development beyond what is inferred from mice. A better understanding of human cerebellar development will not only facilitate improved diagnosis of human cerebellar malformations, but also lead to the development of treatment paradigms for these important neurodevelopmental disorders.


Assuntos
Doenças Cerebelares/patologia , Cerebelo/anormalidades , Cerebelo/crescimento & desenvolvimento , Animais , Humanos , Neurogênese/genética , Neurogênese/fisiologia
10.
J Agric Food Chem ; 66(32): 8602-8614, 2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-30032600

RESUMO

This study was designed to determine whether the tight-junction (TJ) proteins of the blood-brain barrier (BBB) and the PI3K-Akt-mTOR signaling pathway are involved during arsenic (As)-induced autophagy in developing mouse cerebella after exposure to different As concentrations (0, 0.15, 1.5, and 15 mg/L As(III)) during gestational and lactational periods. The dosage was continually given to the pups until postnatal day (PND) 42. Studies conducted at different developmental age points, like PND21, 28, 35, and 42, showed that exposure to As led to a significant decrease in the mRNA-expression levels of TJ proteins (occludin, claudin, ZO-1, and ZO-2), PI3K, Akt, mTOR, and p62, with concomitant increases in Beclin1, LC3I, LC3II, Atg5, and Atg12. Also, As significantly downregulated occludin and mTOR protein-expression levels with concomitant upregulation of Beclin1, LC3, and Atg12 at all the developmental age points. However, no significant alterations were observed in low- and medium-dose-exposed groups at PND42. Histopathological analysis revealed the irregular arrangement of the Purkinje cell layer in the As-exposed mice. Ultrastructural analysis by transmission electron microscopy (TEM) revealed the occurrence of autophagosomes and vacuolated axons in the cerebella of the mice exposed to high doses of As at PND21 and 42, respectively. Finally, we conclude that developmental As exposure significantly alters TJ proteins, resulting an increase in BBB permeability, facilitating the ability of As to cross the BBB and induce autophagy, which might be partly the result of inhibition of the PI3K-Akt-mTOR signaling pathway, in an age-dependent manner (i.e., PND21 mice were found to be more vulnerable to As-induced neurotoxicity), which could be due to the immature BBB allowing As to cross through it. However, the effect was not significant in PND42, which could be due to the developed BBB.


Assuntos
Arsênico/toxicidade , Autofagia/efeitos dos fármacos , Cerebelo/efeitos dos fármacos , Cerebelo/crescimento & desenvolvimento , Serina-Treonina Quinases TOR/metabolismo , Proteínas de Junções Íntimas/metabolismo , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Cerebelo/citologia , Cerebelo/metabolismo , Feminino , Masculino , Camundongos , Ocludina/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína da Zônula de Oclusão-1/metabolismo
11.
Cerebellum ; 17(5): 610-627, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29949094

RESUMO

Impaired cerebellar development is an important determinant of adverse motor and cognitive outcomes in very preterm (VPT) infants. However, longitudinal MRI studies investigating cerebellar maturation from birth through childhood and associated neurodevelopmental outcomes are lacking. We aimed to compare cerebellar volume and growth from term-equivalent age (TEA) to 7 years between VPT (< 30 weeks' gestation or < 1250 g) and full-term children; and to assess the association between these measures, perinatal factors, and 7-year outcomes in VPT children, and whether these relationships varied by sex. In a prospective cohort study of 224 VPT and 46 full-term infants, cerebellar volumes were measured on MRI at TEA and 7 years. Useable data at either time-point were collected for 207 VPT and 43 full-term children. Cerebellar growth from TEA to 7 years was compared between VPT and full-term children. Associations with perinatal factors and 7-year outcomes were investigated in VPT children. VPT children had smaller TEA and 7-year volumes and reduced growth. Perinatal factors were associated with smaller cerebellar volume and growth between TEA and 7 years, namely, postnatal corticosteroids for TEA volume, and female sex, earlier birth gestation, white and deep nuclear gray matter injury for 7-year volume and growth. Smaller TEA and 7-year volumes, and reduced growth were associated with poorer 7-year IQ, language, and motor function, with differential relationships observed for male and female children. Our findings indicate that cerebellar growth from TEA to 7 years is impaired in VPT children and relates to early perinatal factors and 7-year outcomes.


Assuntos
Cerebelo/crescimento & desenvolvimento , Recém-Nascido Prematuro/crescimento & desenvolvimento , Recém-Nascido Prematuro/psicologia , Cerebelo/diagnóstico por imagem , Criança , Seguimentos , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/crescimento & desenvolvimento , Humanos , Modelos Lineares , Estudos Longitudinais , Imagem por Ressonância Magnética , Testes Neuropsicológicos , Tamanho do Órgão , Estudos Prospectivos , Fatores Sexuais , Substância Branca/diagnóstico por imagem , Substância Branca/crescimento & desenvolvimento
12.
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
13.
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
14.
Genome Biol ; 19(1): 68, 2018 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-29855379

RESUMO

BACKGROUND: N6-methyladenosine (m6A) is an important epitranscriptomic mark with high abundance in the brain. Recently, it has been found to be involved in the regulation of memory formation and mammalian cortical neurogenesis. However, while it is now established that m6A methylation occurs in a spatially restricted manner, its functions in specific brain regions still await elucidation. RESULTS: We identify widespread and dynamic RNA m6A methylation in the developing mouse cerebellum and further uncover distinct features of continuous and temporal-specific m6A methylation across the four postnatal developmental processes. Temporal-specific m6A peaks from P7 to P60 exhibit remarkable changes in their distribution patterns along the mRNA transcripts. We also show spatiotemporal-specific expression of m6A writers METTL3, METTL14, and WTAP and erasers ALKBH5 and FTO in the mouse cerebellum. Ectopic expression of METTL3 mediated by lentivirus infection leads to disorganized structure of both Purkinje and glial cells. In addition, under hypobaric hypoxia exposure, Alkbh5-deletion causes abnormal cell proliferation and differentiation in the cerebellum through disturbing the balance of RNA m6A methylation in different cell fate determination genes. Notably, nuclear export of the hypermethylated RNAs is enhanced in the cerebellum of Alkbh5-deficient mice exposed to hypobaric hypoxia. CONCLUSIONS: Together, our findings provide strong evidence that RNA m6A methylation is controlled in a precise spatiotemporal manner and participates in the regulation of postnatal development of the mouse cerebellum.


Assuntos
Adenosina/análogos & derivados , Cerebelo/crescimento & desenvolvimento , RNA/metabolismo , Adenosina/metabolismo , Homólogo AlkB 5 da RNA Desmetilase/genética , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Animais , Hipóxia Celular , Linhagem Celular , Cerebelo/enzimologia , Cerebelo/metabolismo , Feminino , Células HEK293 , Humanos , Masculino , Metilação , Metiltransferases/genética , Metiltransferases/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA/química
15.
Handb Clin Neurol ; 155: 407-413, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29891075

RESUMO

The cerebellum is now at the forefront of research in neuroscience. This is not just a coincidence, occurring about 250 years after the first description of the human cerebellum. The cerebellum contains the majority of neurons in the central nervous system and it is heavily connected with almost all cortical and subcortical areas of the supratentorial region as well as with the brainstem and the spinal cord. Cerebellar circuits are embedded in large-scale networks contributing to motor control and neurocognition. From a phenotypic standpoint, damage to cerebellar lobules interconnected with the sensorimotor cortices leads to a cerebellar motor syndrome, whereas lesions of the posterolateral cerebellum cause cognitive and neuropsychiatric impairments which may or may not be subtle. This topographic rule is valid in children and adults. Midline posterior vermal lesions cause behavioral/affective dysregulation, especially in kids. The extent of the spectrum of human cerebellar disorders is increasingly recognized from the fetus to the elderly, with recognition of consequences for the quality of life and socioeconomic costs due to lifelong morbidity of many cerebellar ataxias/pathologies. The prolonged duration of human cerebellar development makes the cerebellum especially susceptible to developmental disruption, both genetic and nongenetic. This explains the current emphasis on the clarification of the developmental course and impact of the cerebellum. The understanding of how germinal matrix zones and migration of neurons and glial cells end in a highly organized and foliated human cerebellum is essential. This is greatly accelerated by inputs from rodent developmental studies, in particular because cerebellar anatomy is conserved across species. Still, numerous questions on human fetal development remain unanswered. Although both advanced neuroimaging and genetic studies are currently leading to a better definition and understanding of the multitude of cerebellar symptoms, there is a gap, with a great need to develop therapies aiming at first, protection of the cerebellum during development, and second, restoration of cerebellar function in children and in adults. Dynamic profiles of the compensatory processes from newborns to elderly require specific studies.


Assuntos
Doenças Cerebelares/patologia , Cerebelo/embriologia , Cerebelo/crescimento & desenvolvimento , Transtornos Mentais/patologia , Transtornos Cognitivos/patologia , Deficiências do Desenvolvimento/patologia , Feto , Humanos
16.
Cerebellum ; 17(5): 685-691, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29663194

RESUMO

An inherent asymmetry exists between the two centrosomes of a dividing cell. One centrosome is structurally more mature (mother centrosome) than the other (daughter centrosome). Post division, one daughter cell inherits the mother centrosome while the other daughter cell inherits the daughter centrosome. Remarkably, the kind of centrosome inherited is associated with cell fate in several developmental contexts such as in radial glial progenitors in the developing mouse cortex, Drosophila neuroblast divisions and in Drosophila male germline stem cells. However, the role of centrosome inheritance in granule neuron progenitors in the developing cerebellum has not been investigated. Here, we show that mother and daughter centrosomes do exist in these progenitors, and the amount of pericentriolar material (PCM) each centrosome possesses is different. However, we failed to observe any correlation between the fate adopted by the daughter cell and the nature of centrosome it inherited.


Assuntos
Centrossomo/fisiologia , Cerebelo/crescimento & desenvolvimento , Células-Tronco Neurais/fisiologia , Neurônios/fisiologia , Animais , Tronco Encefálico/citologia , Tronco Encefálico/crescimento & desenvolvimento , Tronco Encefálico/metabolismo , Células Cultivadas , Cerebelo/citologia , Cerebelo/metabolismo , Proteínas de Choque Térmico/metabolismo , Imuno-Histoquímica , Mesencéfalo/citologia , Mesencéfalo/crescimento & desenvolvimento , Mesencéfalo/metabolismo , Camundongos , Mitose/fisiologia
17.
Int J Dev Neurosci ; 67: 33-36, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29555564

RESUMO

The cerebellum plays major role in motor coordination and learning. It contains half of the neurons in the brain. Thus, deciphering the mechanisms by which cerebellar neurons are generated is essential to understand the cerebellar functions and the pathologies associated with it. In a recent study, Wojcinski et al. (2017) by using in vivo Cre/loxP technologies reveal that Nestin-expressing progenitors repopulated the external granular cell layer after injury. Depletion of postnatal external granular cell layer is not sufficient to induce motor behavior defects in adults, as the cerebellum recovers these neurons. Strikingly, Nestin-expressing progenitors differentiate into granule cell precursors and mature granule neurons after ablation of perinatal external granular layer, either by irradiation or by genetic ablation. This work identified a novel role of Nestin-expressing progenitors in the cerebellar microenvironment during development, and revealed that extracellular signals can convert specified progenitors into multipotent stem cells. Here, we discuss the findings from this study, and evaluate recent advances in our understanding of the cerebellar neurogenesis.


Assuntos
Lesões Encefálicas/patologia , Cerebelo/patologia , Neurogênese/fisiologia , Animais , Animais Recém-Nascidos , Cerebelo/crescimento & desenvolvimento , Cerebelo/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Nestina/metabolismo , Neurônios/metabolismo , Neurônios/patologia
18.
Adv Exp Med Biol ; 1046: 249-268, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29442326

RESUMO

Zic genes are strongly expressed in the cerebellum. This feature leads to their initial identification and their name "zic," as the abbreviation of "zinc finger protein of the cerebellum." Zic gene function in cerebellar development has been investigated mainly in mice. However, association of heterozygous loss of ZIC1 and ZIC4 with Dandy-Walker malformation, a structural birth defect of the human cerebellum, highlights the clinical relevance of these studies. Two proposed mechanisms for Zic-mediated cerebellar developmental control have been documented: regulation of neuronal progenitor proliferation-differentiation and the patterning of the cerebellar primordium. Clinical studies have also revealed that ZIC1 gain of function mutations contribute to coronal craniosynostosis, a rare skull malformation. The molecular pathways contributing to these phenotypes are not fully explored; however, embryonic interactions with sonic hedgehog signaling, retinoic acid signaling, and TGFß signaling have been described during mouse cerebellar development. Further, Zic1/2 target a multitude of genes associated with cerebellar granule cell maturation during postnatal mouse cerebellar development.


Assuntos
Cerebelo , Craniossinostoses , Síndrome de Dandy-Walker , Células-Tronco Neurais , Transdução de Sinais/genética , Fatores de Transcrição , Animais , Cerebelo/crescimento & desenvolvimento , Cerebelo/fisiologia , Craniossinostoses/genética , Craniossinostoses/metabolismo , Craniossinostoses/patologia , Síndrome de Dandy-Walker/genética , Síndrome de Dandy-Walker/metabolismo , Síndrome de Dandy-Walker/patologia , Humanos , Camundongos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
19.
Neurosci Res ; 129: 24-31, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28711710

RESUMO

Developmental refinement of neuronal connectivity is crucial for proper brain function. In the early phase of development, input fibers arrive at their target areas guided by specific molecular cues and form abundant immature synapses. Then, functionally important synapses are preserved and strengthened by neural activity while unnecessary synapses are eliminated. Afferent synapses in the sensory thalamus, such as from retina to lateral geniculate nucleus, and climbing fiber (CF)-Purkinje cell (PC) synapses in the cerebellum are valuable models for studying this developmental refinement of synaptic connectivity because only a limited number of input fibers innervate a given postsynaptic thalamocortical (TC) neuron or PC. The metabotropic glutamate receptor subtype 1 (mGluR1) is required for the refinement of both afferent-TC neuron and CF-PC synapses. However, mGluR1 functions differently at these synapses. While mGluR1 is critical for elimination of surplus CF-PC synapses in the cerebellum, retinogeniculate synapses require mGluR1 for maintenance of mature connectivity.


Assuntos
Cerebelo/crescimento & desenvolvimento , Corpos Geniculados/crescimento & desenvolvimento , Neurônios/fisiologia , Receptores de Glutamato Metabotrópico/fisiologia , Sinapses/fisiologia , Animais , Camundongos , Células de Purkinje/fisiologia , Vias Visuais/crescimento & desenvolvimento
20.
Toxicol Lett ; 284: 161-169, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29258870

RESUMO

Human fetuses and neonates are particularly vulnerable to methylmercury (MeHg)-induced brain damage and are sensitive even to low exposure levels. Previous work of our group evidence that prenatal exposure to MeHg causes cognitive and behavioral alterations and disrupt hippocampus signaling. The current study aimed to investigate the effect of gestational exposure of rats to MeHg at low doses (1 or 2 mg/kg) on parameters of redox imbalance and key signaling pathways in the cerebellum of their offspring. Pregnant females received MeHg (treated group) or 0.9% saline water (control group) by gavage in alternated days from gestational day 5 (GD5) until parturition and analyzes were proceed in the cerebellum of 30-day-old pups. We found increased lipid peroxidation and protein carbonylation levels as well as decreased SH content in pups prenatally exposed to 2 mg/kg MeHg. In addition, misregulated SOD/catalase activities supported imbalanced redox equilibrium. We found decreased GSK3ß(Ser9) phosphorylation, suggesting activation of this enzyme and dephosphorylation/inhibition of ERK1/2 and JNK pathways. Increased PKAα catalytic subunit could be upstream of hyperphosphorylated c-Raf(Ser259) and downregulated MAPK pathway. In addition, we found raised levels of the Ca2+-dependent protein phosphatase 2 B (PP2B). We also found preserved immunohistochemical staining for both glial fibrillary acidic protein (GFAP) and NeuN in MeHg-exposed pups. Western blot analysis showed unaltered levels of BAX/BCL-XL, BAD/BCL-2 and active caspase 3. Together, these findings support absence of reactive astrocytes, neuronal damage and apoptotic cell death in the cerebellum of MeHg treated pups. The present study provides evidence that prenatal exposure to MeHg leads to later redox imbalance and disrupted signaling mechanisms in the cerebellum of 30-day-old pups potentially predisposing them to long-lasting neurological impairments in CNS.


Assuntos
Cerebelo/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Compostos de Metilmercúrio/toxicidade , Neurônios/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Cerebelo/crescimento & desenvolvimento , Cerebelo/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Feminino , Glicogênio Sintase Quinase 3 beta/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Neurônios/metabolismo , Oxirredução , Gravidez , Carbonilação Proteica/efeitos dos fármacos , Ratos , Ratos Wistar
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