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1.
Biomolecules ; 11(10)2021 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-34680045

RESUMO

Batten disease is a devastating, childhood, rare neurodegenerative disease characterised by the rapid deterioration of cognition and movement, leading to death within ten to thirty years of age. One of the thirteen Batten disease forms, CLN5 Batten disease, is caused by mutations in the CLN5 gene, leading to motor deficits, mental deterioration, cognitive impairment, visual impairment, and epileptic seizures in children. A characteristic pathology in CLN5 Batten disease is the defects in lysosomes, leading to neuronal dysfunction. In this study, we aimed to investigate the lysosomal changes in CLN5-deficient human neurons. We used an induced pluripotent stem cell system, which generates pure human cortical-like glutamatergic neurons. Using CRISPRi, we inhibited the expression of CLN5 in human neurons. The CLN5-deficient human neurons showed reduced acidic organelles and reduced lysosomal enzyme activity measured by microscopy and flow cytometry. Furthermore, the CLN5-deficient human neurons also showed impaired lysosomal movement-a phenotype that has never been reported in CLN5 Batten disease. Lysosomal trafficking is key to maintain local degradation of cellular wastes, especially in long neuronal projections, and our results from the human neuronal model present a key finding to understand the underlying lysosomal pathology in neurodegenerative diseases.


Assuntos
Proteínas de Membrana Lisossomal/genética , Doenças Neurodegenerativas/genética , Lipofuscinoses Ceroides Neuronais/genética , Neurônios/metabolismo , Adolescente , Adulto , Sistemas CRISPR-Cas/genética , Catepsina B/farmacologia , Linhagem Celular , Córtex Cerebelar/crescimento & desenvolvimento , Córtex Cerebelar/metabolismo , Criança , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Proteínas de Membrana Lisossomal/antagonistas & inibidores , Lisossomos/genética , Mutação/genética , Doenças Neurodegenerativas/complicações , Doenças Neurodegenerativas/fisiopatologia , Lipofuscinoses Ceroides Neuronais/complicações , Lipofuscinoses Ceroides Neuronais/fisiopatologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fenótipo , Adulto Jovem
2.
Genes (Basel) ; 12(10)2021 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-34680993

RESUMO

Down syndrome (DS), also known as trisomy 21, is the most frequent genetic cause of intellectual disability. Although the mechanism remains unknown, delayed brain development is assumed to be involved in DS intellectual disability. Analyses with human with DS and mouse models have shown that defects in embryonic cortical neurogenesis may lead to delayed brain development. Cre-loxP-mediated chromosomal engineering has allowed the generation of a variety of mouse models carrying various partial Mmu16 segments. These mouse models are useful for determining genotype-phenotype correlations and identifying dosage-sensitive genes involved in the impaired neurogenesis. In this review, we summarize several candidate genes and pathways that have been linked to defective cortical neurogenesis in DS.


Assuntos
Encéfalo/metabolismo , Síndrome de Down/genética , Desenvolvimento Embrionário/genética , Neurogênese/genética , Animais , Animais Geneticamente Modificados/genética , Animais Geneticamente Modificados/crescimento & desenvolvimento , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Córtex Cerebelar/crescimento & desenvolvimento , Modelos Animais de Doenças , Síndrome de Down/patologia , Genótipo , Humanos , Camundongos
3.
Proc Natl Acad Sci U S A ; 118(23)2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34088841

RESUMO

Cerebellar granule cells (GrCs) are usually regarded as a uniform cell type that collectively expands the coding space of the cerebellum by integrating diverse combinations of mossy fiber inputs. Accordingly, stable molecularly or physiologically defined GrC subtypes within a single cerebellar region have not been reported. The only known cellular property that distinguishes otherwise homogeneous GrCs is the correspondence between GrC birth timing and the depth of the molecular layer to which their axons project. To determine the role birth timing plays in GrC wiring and function, we developed genetic strategies to access early- and late-born GrCs. We initiated retrograde monosynaptic rabies virus tracing from control (birth timing unrestricted), early-born, and late-born GrCs, revealing the different patterns of mossy fiber input to GrCs in vermis lobule 6 and simplex, as well as to early- and late-born GrCs of vermis lobule 6: sensory and motor nuclei provide more input to early-born GrCs, while basal pontine and cerebellar nuclei provide more input to late-born GrCs. In vivo multidepth two-photon Ca2+ imaging of axons of early- and late-born GrCs revealed representations of diverse task variables and stimuli by both populations, with modest differences in the proportions encoding movement, reward anticipation, and reward consumption. Our results suggest neither organized parallel processing nor completely random organization of mossy fiber→GrC circuitry but instead a moderate influence of birth timing on GrC wiring and encoding. Our imaging data also provide evidence that GrCs can represent generalized responses to aversive stimuli, in addition to recently described reward representations.


Assuntos
Córtex Cerebelar/crescimento & desenvolvimento , Fibras Nervosas/metabolismo , Animais , Animais Recém-Nascidos , Córtex Cerebelar/virologia , Camundongos , Camundongos Transgênicos , Fibras Nervosas/virologia , Vírus da Raiva/metabolismo
4.
Semin Cell Dev Biol ; 118: 14-23, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33863642

RESUMO

During cortical development and throughout adulthood, oligodendrocytes add myelin internodes to glutamatergic projection neurons and GABAergic inhibitory neurons. In addition to directing node of Ranvier formation, to enable saltatory conduction and influence action potential transit time, oligodendrocytes support axon health by communicating with axons via the periaxonal space and providing metabolic support that is particularly critical for healthy ageing. In this review we outline the timing of oligodendrogenesis in the developing mouse and human cortex and describe the important role that oligodendrocytes play in sustaining and modulating neuronal function. We also provide insight into the known and speculative impact that myelination has on cortical axons and their associated circuits during the developmental critical periods and throughout life, particularly highlighting their life-long role in learning and remembering.


Assuntos
Córtex Cerebelar/crescimento & desenvolvimento , Bainha de Mielina/fisiologia , Plasticidade Neuronal/fisiologia , Oligodendroglia/fisiologia , Animais , Humanos , Camundongos
5.
Anat Rec (Hoboken) ; 304(2): 413-424, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32396712

RESUMO

We immunohistochemically characterized postnatal changes in cerebellar cortical cytoarchitectures in ferrets using markers for cerebellar cortical neurons and glial cells. Although 10 lobules of the vermis were already observed on postnatal day (PD) 4, Purkinje cells were still arrayed into two to three layers. Purkinje cells were aligned in a monolayer by PD 10 and formed mature shapes on PD 42 by developing their dendritic arbors. Parvalbumin immunostaining revealed relatively slower maturation of Purkinje cells in the Lobule X cortex than in other lobules. Basket and stellate cells emerged in the molecular layer on PDs 21 and 42, respectively. Rosette-like arranged glutamate decarboxylase 65 and 67-positive puncta were observed in the inner granular layer (IGL) on PD 21. Proliferating cell nuclear antigen immunostaining appeared in the outer zone of the external granular layer (EGL) containing progenitors of granular neurons on PDs 4-21. Bergmann glial processes extending vertically through the molecular layer and EGL were visible with GFAP immunostaining on PD 10 and thereafter. Their somata, aligned in the Purkinje cell layer, showed immunopositivity to Sox2 already on PD 4 and subsequently to S100 protein on PD 10. Sox2-positive cells were found sparsely in the IGL. Few of them were NeuN positive on PD 90, predicting the possibility of adult neurogenesis. These immunohistochemical results revealed that ferrets underwent cerebellar cortical histogenesis during their postnatal life in sequences. Relatively slow development or maturation of the ferret cerebellum was revealed by the timing of the monolayer alignment and morphological maturation of Purkinje cells.


Assuntos
Córtex Cerebelar/metabolismo , Neurônios/metabolismo , Parvalbuminas/metabolismo , Animais , Córtex Cerebelar/crescimento & desenvolvimento , Furões , Imuno-Histoquímica , Masculino , Neuroglia/metabolismo , Células de Purkinje/metabolismo
7.
J Comp Neurol ; 528(1): 61-80, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31246278

RESUMO

The extracellular matrix is essential for brain development, lamination, and synaptogenesis. In particular, the basement membrane below the pial meninx (pBM) is required for correct cortical development. The last step in the catabolism of the most abundant protein in pBM, collagen Type IV, requires prolidase, an exopeptidase cleaving the imidodipeptides containing pro or hyp at the C-terminal end. Mutations impairing prolidase activity lead in humans to the rare disease prolidase deficiency characterized by severe skin ulcers and mental impairment. Thus, the dark-like (dal) mouse, in which the prolidase is knocked-out, was used to investigate whether the deficiency of prolidase affects the neuronal maturation during development of a brain cortex area. Focusing on the cerebellar cortex, thinner collagen fibers and disorganized pBM were found. Aberrant cortical granule cell proliferation and migration occurred, associated to defects in brain lamination, and in particular in maturation of Purkinje neurons and formation of synaptic contacts. This study deeply elucidates a link between prolidase activity and neuronal maturation shedding new light on the molecular basis of functional aspects in the prolidase deficiency.


Assuntos
Córtex Cerebelar/enzimologia , Córtex Cerebelar/crescimento & desenvolvimento , Dipeptidases/metabolismo , Matriz Extracelular/enzimologia , Animais , Animais Recém-Nascidos , Córtex Cerebelar/química , Dipeptidases/análise , Matriz Extracelular/química , Imunofluorescência/métodos , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos CBA , Camundongos Transgênicos
8.
Elife ; 82019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31742552

RESUMO

For neural systems to function effectively, the numbers of each cell type must be proportioned properly during development. We found that conditional knockout of the mouse homeobox genes En1 and En2 in the excitatory cerebellar nuclei neurons (eCN) leads to reduced postnatal growth of the cerebellar cortex. A subset of medial and intermediate eCN are lost in the mutants, with an associated cell non-autonomous loss of their presynaptic partner Purkinje cells by birth leading to proportional scaling down of neuron production in the postnatal cerebellar cortex. Genetic killing of embryonic eCN throughout the cerebellum also leads to loss of Purkinje cells and reduced postnatal growth but throughout the cerebellar cortex. Thus, the eCN play a key role in scaling the size of the cerebellum by influencing the survival of their Purkinje cell partners, which in turn regulate production of granule cells and interneurons via the amount of sonic hedgehog secreted.


Assuntos
Proliferação de Células , Córtex Cerebelar/crescimento & desenvolvimento , Núcleos Cerebelares/citologia , Células de Purkinje/fisiologia , Animais , Técnicas de Inativação de Genes , Proteínas de Homeodomínio/genética , Camundongos , Proteínas do Tecido Nervoso/deficiência
9.
Cell Death Dis ; 10(8): 579, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31371703

RESUMO

Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine protein kinase that regulates brain development and neurodegeneration. Cdk5 is activated by p25 that is generated from calpain-dependent cleavage of p35. The generation of p25 is responsible for the aberrant hyper-activation of Cdk5, which causes neurodegeneration. Using in vitro assays, we discovered that F-box/WD repeat-containing protein 7 (Fbxw7) is a new substrate of Cdk5. Additionally, Cdk5-dependent phosphorylation of Fbxw7 was detected in the presence of p25, and two amino acid residues (S349 and S372) were determined to be major phosphorylation sites. This phosphorylation was eventually linked to decreased stability of Fbxw7. Using a culture model of cortical neurons challenged with glutamate, we confirmed that decreased stability of Fbxw7 was indeed Cdk5-dependent. Furthermore, diminished levels of Fbxw7 led to increased levels of transcription factor AP-1 (c-Jun), a known substrate of Fbxw7. Given that previous reports demonstrate that c-Jun plays a role in accelerating neuronal apoptosis in these pathological models, our data support the concepts of a molecular cascade in which Cdk5-mediated phosphorylation of Fbxw7 negatively regulates Fbxw7 expression, thereby contributing to neuronal cell death following glutamate-mediated excitotoxicity.


Assuntos
Encéfalo/metabolismo , Proteína 7 com Repetições F-Box-WD/genética , Degeneração Neural/genética , Neurônios/metabolismo , Animais , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Morte Celular/genética , Córtex Cerebelar/crescimento & desenvolvimento , Córtex Cerebelar/metabolismo , Córtex Cerebelar/patologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Ácido Glutâmico/metabolismo , Células HEK293 , Humanos , Camundongos , Degeneração Neural/patologia , Sistema Nervoso/crescimento & desenvolvimento , Sistema Nervoso/metabolismo , Neurônios/patologia , Fosforilação/genética , Fosfotransferases/genética , Cultura Primária de Células , Estabilidade Proteica
10.
Nat Commun ; 10(1): 3028, 2019 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31292434

RESUMO

Cerebellar neuronal progenitors undergo a series of divisions before irreversibly exiting the cell cycle and differentiating into neurons. Dysfunction of this process underlies many neurological diseases including ataxia and the most common pediatric brain tumor, medulloblastoma. To better define the pathways controlling the most abundant neuronal cells in the mammalian cerebellum, cerebellar granule cell progenitors (GCPs), we performed RNA-sequencing of GCPs exiting the cell cycle. Time-series modeling of GCP cell cycle exit identified downregulation of activity of the epigenetic reader protein Brd4. Brd4 binding to the Gli1 locus is controlled by Casein Kinase 1δ (CK1 δ)-dependent phosphorylation during GCP proliferation, and decreases during GCP cell cycle exit. Importantly, conditional deletion of Brd4 in vivo in the developing cerebellum induces cerebellar morphological deficits and ataxia. These studies define an essential role for Brd4 in cerebellar granule cell neurogenesis and are critical for designing clinical trials utilizing Brd4 inhibitors in neurological indications.


Assuntos
Ataxia Cerebelar/genética , Córtex Cerebelar/crescimento & desenvolvimento , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Animais , Animais Recém-Nascidos , Caseína Quinase Idelta , Ciclo Celular/fisiologia , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Ataxia Cerebelar/patologia , Córtex Cerebelar/citologia , Córtex Cerebelar/patologia , Modelos Animais de Doenças , Regulação para Baixo , Humanos , Camundongos , Camundongos Knockout , Neurônios/fisiologia , Proteínas Nucleares/genética , Fosforilação/fisiologia , Cultura Primária de Células , Fatores de Transcrição/genética , Proteína GLI1 em Dedos de Zinco/metabolismo
11.
Cell Death Dis ; 9(10): 999, 2018 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-30250269

RESUMO

The establishment of functional neuronal connectivity is dependent on the neuronal migration and the accurate positioning of neurons in the developing brain. Abnormal neuronal migration can trigger neuronal maturation defects and apoptosis. However, many genetic bases remain unclear in neuronal migration disorders during brain development. In this study, we reported that MARVELD1-defected mice displayed motor and cognitive dysfunction resulting from aberrant neuronal migration during brain development. The laminar organization of the cerebral cortex and cerebellum in MARVELD1 knockout (KO) mice is disrupted, indicating impaired radial neuronal migration. Furthermore, we used the cerebellum as a model to explore the radial neuronal migration processes, and the results demonstrated that the proper neuronal migration depended on MARVELD1 expression in glial cells of the developing brain. MARVELD1 suppressed the expression of ITGB1 and FAK Tyr397 phosphorylation in glia-dependent manner. The inhibition of the MARVELD1/ITGB1/FAK signalling pathway in MARVELD1 KO mice could reverse the defects in neuronal migration in vitro. Our findings revealed that MARVELD1 regulated neuronal migration by mediating the formation of glial fibres and ITGB1/FAK signalling pathway. The depletion of MARVELD1 during mouse brain development led to the abnormity of motor and cognition functions.


Assuntos
Movimento Celular/fisiologia , Córtex Cerebelar/crescimento & desenvolvimento , Disfunção Cognitiva/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Movimento/fisiologia , Neuroglia/metabolismo , Neurônios/metabolismo , Animais , Córtex Cerebelar/metabolismo , Teste de Esforço , Quinase 1 de Adesão Focal/metabolismo , Técnicas de Inativação de Genes , Integrina beta1/metabolismo , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/genética , Neurogênese/fisiologia , Fosforilação , Células de Purkinje/metabolismo
12.
Brain Behav Evol ; 91(3): 158-169, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30099464

RESUMO

Cerebral cortex and cerebellar cortex both vary enormously across species in their size and complexity of convolutions. We discuss the development and evolution of cortical structures in terms of anatomy and functional organization. We propose that the distinctive shapes of cerebral and cerebellar cortex can be explained by relatively few developmental processes, notably including mechanical tension along axons and dendrites. Regarding functional organization, we show how maps of myelin content in cerebral cortex are evolutionarily conserved across primates but differ in the proportion of cortex devoted to sensory, cognitive, and other functions. We summarize recent progress and challenges in (i) parcellating cerebral cortex into a mosaic of distinct areas, (ii) distinguishing cortical areas that correspond across species from those that are present in one species but not another, and (iii) using this information along with surface-based interspecies registration to gain deeper insights into cortical evolution. We also comment on the methodological challenges imposed by the differences in anatomical and functional organization of cerebellar cortex relative to cerebral cortex.


Assuntos
Evolução Biológica , Córtex Cerebelar/anatomia & histologia , Córtex Cerebelar/crescimento & desenvolvimento , Córtex Cerebral/anatomia & histologia , Córtex Cerebral/crescimento & desenvolvimento , Animais , Humanos
13.
Eur. j. anat ; 22(4): 345-354, jul. 2018. ilus, tab
Artigo em Inglês | IBECS | ID: ibc-179098

RESUMO

Gibberellic acid (GA3) is a plant growth regulator, widely used in agriculture in Egypt. The goal of this study was to illustrate the histopathological effects of (GA3) on the growing cerebellar cortex and the possible ameliorative effect of vitamin C. Fifty female Sprague-Dawly rats were classified into the following groups: Group I (control group); Group II (GA3-treated group), which received intra-gastric daily dose of GA3 55 mg/kg from the 14th day of pregnancy until the day 14 after delivery; Group III (GA3 & Vitamin C treated group), which received intra-gastric daily dose GA3, 55 mg/kg simultaneously with 100 mg of Vitamin C /kg from the 14th day of pregnancy till day 14 after delivery; and Group IV (Vitamin C-treated group), which received intra-gastric daily dose 100 mg of Vitamin C / kg from the 14th day of pregnancy till day 14 after delivery. One month after delivery, cerebella of pups from all groups were extracted and examined. The cerebellar cortex of GA3-treated group revealed degenerated and displaced Purkinje and granular nerve cells with prominent spongiosis in the molecular layer. Vitamin C administration resulted in marked regression of the previously mentioned neurotoxic effects. In conclusion: results of the current study revealed that maternal exposure to GA3 during pregnancy and lactation caused delayed development of the offsprings' cerebellar cortex. The co-administration of Vitamin C greatly reduced these neuro-toxic effects of GA3 exposure


No disponible


Assuntos
Animais , Ratos , Gravidez , Giberelinas/toxicidade , Córtex Cerebelar/anatomia & histologia , Ácido Ascórbico/uso terapêutico , Albinismo , Giberelinas , Córtex Cerebelar/crescimento & desenvolvimento , Córtex Cerebelar/fisiopatologia , Gravidez/fisiologia , Gravidez/metabolismo
14.
Brain Res ; 1686: 10-18, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29462607

RESUMO

We investigated the effects of the gestational administration of lead (Pb) and ascorbic acid on cerebellar development. Pregnant female rats were randomly assigned to the control, Pb, or Pb plus ascorbic acid (PA) groups; six offspring per cage were randomly selected for analysis. Compared to the control group, fewer Purkinje cells were observed in the Pb-exposed pups at postnatal day 21. However, co-administrating Pb and ascorbic acid inhibited the Pb-induced reduction in Purkinje cells. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining, which detected DNA fragmentation in the dying cells, showed more TUNEL-positive cells in the Pb group, while co-treatment with Pb and ascorbic acid mitigated the Pb-induced cellular degeneration. Using immunohistochemistry and immunoblotting, we additionally found that Pb exposure induced a rise in the apoptotic factor Bax in the cerebellum, while Pb plus ascorbic acid treatment ameliorated this Bax induction. Since, Pb competes with the iron in the cell and the accumulation of free iron triggers oxidative stress, we performed iron staining, which revealed that ascorbic acid prevented the Pb-induced rises in iron-reactive cells and iron-reactivity. The anti-oxidant enzyme manganese-dependent superoxide dismutase showed change patterns that were similar to those of iron in the cerebellum. Finally, the pups' blood Pb levels were highest in the Pb group but were reduced in the PA group. Our findings suggest that ascorbic acid effectively ameliorates Pb-induced apoptosis and oxidative stress in the cerebellum. The present results imply that ascorbic acid treatment during pregnancy may protect against Pb-mediated developmental impairments in the cerebellum.


Assuntos
Apoptose/efeitos dos fármacos , Ácido Ascórbico/farmacologia , Córtex Cerebelar/efeitos dos fármacos , Cerebelo/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Animais , Animais Recém-Nascidos , Córtex Cerebelar/crescimento & desenvolvimento , Cerebelo/crescimento & desenvolvimento , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/crescimento & desenvolvimento , Masculino , Estresse Oxidativo/efeitos dos fármacos , Gravidez , Células de Purkinje/metabolismo , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo
15.
Cerebellum ; 17(1): 62-71, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29149443

RESUMO

The cerebellum arguably constitutes one of the best characterized central nervous circuits, and its structure, cellular function, and histogenesis have been described in exceptional quantitative detail. A notable exception to this is the development of its inhibitory interneurons, and in particular the extensive migrations of future basket and stellate cells. Here, we used acute slices from 8-day-old mice to assess the migration of Pax2-EGFP-tagged precursors of these cells en route to the molecular layer during their transit through the nascent cerebellar cortex. We document that movement of these cells is highly directed. Their speed and directional persistence are larger in the nascent granule cell layer than in the molecular layer. And they migrate periodically, with periods of effective, directed translocation separated by bouts of rather local movement. Finally, we document that the arrangement of these cells in the adult molecular layer is characterized by clustering. These data are discussed with a focus on potential generative mechanisms for the developmental pattern observed.


Assuntos
Movimento Celular/fisiologia , Córtex Cerebelar/citologia , Interneurônios/fisiologia , Células-Tronco Neurais/fisiologia , Animais , Animais Recém-Nascidos , Córtex Cerebelar/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fator de Transcrição PAX2/genética , Fator de Transcrição PAX2/metabolismo
16.
Dev Biol ; 432(1): 165-177, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-28974424

RESUMO

Cerebellar growth and foliation require the Hedgehog-driven proliferation of granule cell precursors (GCPs) in the external granule layer (EGL). However, that increased or extended GCP proliferation generally does not elicit ectopic folds suggests that additional determinants control cortical expansion and foliation during cerebellar development. Here, we find that genetic loss of the serine-threonine kinase Liver Kinase B1 (Lkb1) in GCPs increased cerebellar cortical size and foliation independent of changes in proliferation or Hedgehog signaling. This finding is unexpected given that Lkb1 has previously shown to be critical for Hedgehog pathway activation in cultured cells. Consistent with unchanged proliferation rate of GCPs, the cortical expansion of Lkb1 mutants is accompanied by thinning of the EGL. The plane of cell division, which has been implicated in diverse processes from epithelial surface expansions to gyrification of the human cortex, remains unchanged in the mutants when compared to wild-type controls. However, we find that Lkb1 mutants display delayed radial migration of post-mitotic GCPs that coincides with increased cortical size, suggesting that aberrant cell migration may contribute to the cortical expansion and increase foliation. Taken together, our results reveal an important role for Lkb1 in regulating cerebellar cortical size and foliation in a Hedgehog-independent manner.


Assuntos
Movimento Celular/fisiologia , Grânulos Citoplasmáticos/fisiologia , Proteínas Serina-Treonina Quinases/fisiologia , Proteínas Quinases Ativadas por AMP , Animais , Diferenciação Celular/fisiologia , Divisão Celular/fisiologia , Córtex Cerebelar/citologia , Córtex Cerebelar/enzimologia , Córtex Cerebelar/crescimento & desenvolvimento , Córtex Cerebelar/metabolismo , Grânulos Citoplasmáticos/enzimologia , Grânulos Citoplasmáticos/metabolismo , Proteínas Hedgehog/metabolismo , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Neurônios/citologia , Neurônios/enzimologia , Neurônios/metabolismo , Organogênese/fisiologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/fisiologia
17.
Neural Plast ; 2017: 6595740, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28894610

RESUMO

The formation of the complex cerebellar cortical circuits follows different phases, with initial synaptogenesis and subsequent processes of refinement guided by a variety of mechanisms. The regularity of the cellular and synaptic organization of the cerebellar cortex allowed detailed studies of the structural plasticity mechanisms underlying the formation of new synapses and retraction of redundant ones. For the attainment of the monoinnervation of the Purkinje cell by a single climbing fiber, several signals are involved, including electrical activity, contact signals, homosynaptic and heterosynaptic interaction, calcium transients, postsynaptic receptors, and transduction pathways. An important role in this developmental program is played by serotonergic projections that, acting on temporally and spatially regulated postsynaptic receptors, induce and modulate the phases of synaptic formation and maturation. In the adult cerebellar cortex, many developmental mechanisms persist but play different roles, such as supporting synaptic plasticity during learning and formation of cerebellar memory traces. A dysfunction at any stage of this process can lead to disorders of cerebellar origin, which include autism spectrum disorders but are not limited to motor deficits. Recent evidence in animal models links impairment of Purkinje cell function with autism-like symptoms including sociability deficits, stereotyped movements, and interspecific communication by vocalization.


Assuntos
Transtorno Autístico/patologia , Córtex Cerebelar/crescimento & desenvolvimento , Rede Nervosa/crescimento & desenvolvimento , Serotonina/metabolismo , Animais , Transtorno Autístico/metabolismo , Córtex Cerebelar/metabolismo , Córtex Cerebelar/patologia , Modelos Animais de Doenças , Humanos , Camundongos , Rede Nervosa/metabolismo , Rede Nervosa/patologia , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Neurônios/patologia , Sinapses/fisiologia
18.
ASN Neuro ; 9(4): 1759091417720582, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28735558

RESUMO

Nicotinic acetylcholine receptors (nAChRs) are cationic channels of the neuronal cell membrane, differentially expressed in the central nervous system which, when activated by endogenous acetylcholine or exogenous nicotine, are able to enhance cholinergic transmission. The aim of this study was to investigate in human perinatal age the immunohistochemical expression of the α7-nAChR subtype, given its involvement in neuronal differentiation and its significant vulnerability to the toxic effects of nicotine. Thirty fetuses (with a gestational age between 25 and 40 weeks) and 35 infants (1-6 months old), suddenly died of known (controls) and unknown causes (unexplained deaths), with smoking and nonsmoking mothers, were included in this study. A negative or low immunoexpression of α7-nAChRs, indicative of their inactivation, was observed in the granular layers of the cerebellar cortex in 66% of the sudden unexplained perinatal deaths and 11% of the controls. A high correlation was also observed between these findings and maternal smoking. Apart from the well-known adverse effects of nicotine exposure during pregnancy, it may also cause significant alterations in cerebellar cholinergic transmission in areas of the brain involved in vital functions. These events may give us insights into the pathogenetic mechanisms leading to sudden unexplained fetal and infant death.


Assuntos
Córtex Cerebelar/crescimento & desenvolvimento , Córtex Cerebelar/metabolismo , Morte Fetal , Morte Súbita do Lactente , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Tronco Encefálico/crescimento & desenvolvimento , Tronco Encefálico/metabolismo , Tronco Encefálico/patologia , Córtex Cerebelar/patologia , Feminino , Humanos , Imuno-Histoquímica , Lactente , Recém-Nascido , Masculino , Gravidez , Complicações na Gravidez , Fumar
19.
Neurotox Res ; 31(1): 46-62, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27566479

RESUMO

Valproic acid (VPA) is used to establish models of experimental autism. The present study investigated the developmental exposure effect of VPA on postnatal hippocampal neurogenesis in accordance with the exposure scheme of OECD Test Guideline 426 adopted for developmental neurotoxicity. Pregnant rats were administered drinking water containing 0, 667, or 2000 ppm VPA from gestational day 6 until day 21 post-delivery. In the subgranular zone (SGZ) and granule cell layer (GCL) of offspring, the number of granule cell lineage subpopulations remained unchanged upon weaning. However, in the hilus of the dentate gyrus, the number of reelin+ interneurons decreased at ≥667 ppm, and the number of PVALB+ or GAD67+ interneurons decreased at 2000 ppm. Conversely, Reln and Gad1 transcript levels increased at 2000 ppm, but Pvalb and Grin2d decreased, in the dentate gyrus. At the adult stage, PCNA+ proliferating SGZ cells, NeuN+ postmitotic SGZ/GCL neurons, and ARC+ or COX2+ GCL neurons increased at ≥667 ppm. In the dentate hilus, decreases in GAD67+ interneuron subpopulations and Grin2d transcript levels sustained at 2000 ppm. These results suggested that VPA primarily targets interneurons by developmental exposure, and this is followed by late effects on granule cell lineages, likely by influencing SGZ cell proliferation and synaptic plasticity. A reduced population of reelin+ or PVALB+ interneurons did not affect distribution of granule cell lineage subpopulations upon weaning. The late effect on neurogenesis, which resulted in increased GCL neurons, might be the result of a sustained decrease in GAD67+ interneurons expressing NR2D encoded by Grin2d.


Assuntos
Giro Denteado/efeitos dos fármacos , Interneurônios/efeitos dos fármacos , Exposição Materna , Neurogênese/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Ácido Valproico/toxicidade , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Movimento Celular/efeitos dos fármacos , Córtex Cerebelar/efeitos dos fármacos , Córtex Cerebelar/crescimento & desenvolvimento , Córtex Cerebelar/metabolismo , Córtex Cerebelar/patologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Giro Denteado/crescimento & desenvolvimento , Giro Denteado/metabolismo , Giro Denteado/patologia , Modelos Animais de Doenças , Água Potável , Feminino , Interneurônios/metabolismo , Interneurônios/patologia , Masculino , Neurogênese/fisiologia , Gravidez , Distribuição Aleatória , Ratos , Proteína Reelina , Nicho de Células-Tronco/efeitos dos fármacos , Nicho de Células-Tronco/fisiologia
20.
Metab Brain Dis ; 31(6): 1369-1380, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27389246

RESUMO

There is sufficient evidence that diabetes during pregnancy is associated with a higher risk of neurodevelopmental anomalies including learning deficits, behavioral problems and motor dysfunctions in the offspring. Synaptophysin (SYP) is an integral membrane protein of synaptic vesicles and is considered as a marker for synaptogenesis and synaptic density. This study aimed to examine the effects of maternal diabetes in pregnancy on the expression and localization of SYP in the developing rat cerebellum. Wistar female rats were maintained diabetic from a week before pregnancy through parturition and male offspring was euthanized at postnatal day (P) 0, 7, and 14. The results revealed a significant down-regulation in the mRNA expression of SYP in the offspring born to diabetic animals at both P7 and P14 (P < 0.05 each). One week after birth, there was a significant reduction in the localization of SYP expression in the external granular (EGL) and in the molecular (ML) layers of neonates born to diabetic animals (P < 0.05 each). We also found a marked decrease in the expression of SYP in all of the cerebellar cortical layers of STZ-D group pups at P14 (P < 0.05 each). Moreover, our results revealed no significant changes in either expression or localization of SYP in insulin-treated group pups when compared with the controls (P ≥ 0.05 each). The present study demonstrated that maternal diabetes has adverse effects on the synaptogenesis in the offspring's cerebellum. Furthermore, the rigid maternal blood glucose control in the most cases normalized these negative impacts.


Assuntos
Córtex Cerebelar/crescimento & desenvolvimento , Córtex Cerebelar/metabolismo , Diabetes Mellitus Experimental/metabolismo , Sinaptofisina/biossíntese , Animais , Glicemia/metabolismo , Córtex Cerebelar/química , Diabetes Mellitus Experimental/genética , Feminino , Expressão Gênica , Masculino , Gravidez , Distribuição Aleatória , Ratos , Ratos Wistar , Sinaptofisina/análise , Sinaptofisina/genética
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