Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 57
Filtrar
Mais filtros

Bases de dados
Tipo de documento
Intervalo de ano de publicação
1.
J Neurosci ; 41(13): 2899-2910, 2021 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-33637561

RESUMO

The addition of new neurons to existing neural circuits in the adult brain remains of great interest to neurobiology because of its therapeutic implications. The premier model for studying this process has been the hippocampal dentate gyrus in mice, where new neurons are added to mature circuits during adulthood. Notably, external factors such as an enriched environment (EE) and exercise markedly increase hippocampal neurogenesis. Here, we demonstrate that EE acts by increasing fibroblast growth factor receptor (FGFR) function autonomously within neurogenic cells to expand their numbers in adult male and female mice. FGFRs activated by EE signal through their mediators, FGFR substrate (FRS), to induce stem cell proliferation, and through FRS and phospholipase Cγ to increase the number of adult-born neurons, providing a mechanism for how EE promotes adult neurogenesis.SIGNIFICANCE STATEMENT How the environment we live in affects cognition remains poorly understood. In the current study, we explore the mechanism underlying the effects of an enriched environment on the production of new neurons in the adult hippocampal dentate gyrus, a brain area integral in forming new memories. A mechanism is provided for how neural precursor cells in the adult mammalian dentate gyrus respond to an enriched environment to increase their neurogenic output. Namely, an enriched environment acts on stem and progenitor cells by activating fibroblast growth factor receptor signaling through phospholipase Cγ and FGF receptor substrate proteins to expand the pool of precursor cells.


Assuntos
Meio Ambiente , Hipocampo/citologia , Hipocampo/metabolismo , Células-Tronco Neurais/metabolismo , Neurogênese/fisiologia , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Fatores Etários , Animais , Feminino , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Receptores de Fatores de Crescimento de Fibroblastos/genética
2.
PLoS Biol ; 16(3): e2002988, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29534062

RESUMO

How asymmetries in motor behavior become established normally or atypically in mammals remains unclear. An established model for motor asymmetry that is conserved across mammals can be obtained by experimentally inducing asymmetric striatal dopamine activity. However, the factors that can cause motor asymmetries in the absence of experimental manipulations to the brain remain unknown. Here, we show that mice with inner ear dysfunction display a robust left or right rotational preference, and this motor preference reflects an atypical asymmetry in cortico-striatal neurotransmission. By unilaterally targeting striatal activity with an antagonist of extracellular signal-regulated kinase (ERK), a downstream integrator of striatal neurotransmitter signaling, we can reverse or exaggerate rotational preference in these mice. By surgically biasing vestibular failure to one ear, we can dictate the direction of motor preference, illustrating the influence of uneven vestibular failure in establishing the outward asymmetries in motor preference. The inner ear-induced striatal asymmetries identified here intersect with non-ear-induced asymmetries previously linked to lateralized motor behavior across species and suggest that aspects of left-right brain function in mammals can be ontogenetically influenced by inner ear input. Consistent with inner ear input contributing to motor asymmetry, we also show that, in humans with normal ear function, the motor-dominant hemisphere, measured as handedness, is ipsilateral to the ear with weaker vestibular input.


Assuntos
Lateralidade Funcional , Doenças do Labirinto/complicações , Atividade Motora/fisiologia , Animais , Comportamento Animal , Humanos , Camundongos , Transmissão Sináptica/fisiologia , Vestíbulo do Labirinto/fisiologia , Vestíbulo do Labirinto/fisiopatologia
3.
Glia ; 68(3): 617-630, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31670856

RESUMO

FGF signaling is important for numerous cellular processes and produces diverse cellular responses. Our recent studies using mice conditionally lacking FGF-Receptor-1 (Fgfr1) or Fgfr2 during different stages of myelinogenesis revealed that Fgfr signaling is first required embryonically for the specification of oligodendrocyte progenitors (OPCs) and then later postnatally for the growth of the myelin sheath during active myelination but not for OPC proliferation, differentiation, or ensheathment of axons. What intracellular signal transduction pathways are recruited immediately downstream of Fgfrs and mediate these distinct developmentally regulated stage-specific responses remain unclear. The adapter protein Fibroblast-Growth-Factor-Receptor-Substrate-2 (Frs2) is considered a key immediate downstream target of Fgfrs. Therefore, here, we investigated the in vivo role of Frs adapters in the oligodendrocyte lineage cells, using a novel genetic approach where mice were engineered to disrupt binding of Frs2 to Fgfr1 or Fgfr2, thus specifically uncoupling Frs2 and Fgfr signaling. In addition, we used conditional mutants with complete ablation of Frs2 and Frs3. We found that Frs2 is required for specification of OPCs in the embryonic telencephalon downstream of Fgfr1. In contrast, Frs2 is largely dispensable for transducing Fgfr2-mediated signals for the growth of the myelin sheath during postnatal myelination, implying the potential involvement of other adapters downstream of Fgfr2 for this function. Together, our data demonstrate a developmental stage-specific function of Frs2 in the oligodendrocyte lineage cells. This contextual requirement of adapter proteins, downstream of Fgfrs, could partly explain the distinct responses elicited by the activation of Fgfrs during different stages of myelinogenesis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Linhagem da Célula/fisiologia , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Animais , Diferenciação Celular/fisiologia , Células Cultivadas , Fatores de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/fisiologia
4.
Proc Natl Acad Sci U S A ; 113(45): 12697-12702, 2016 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-27791114

RESUMO

Piwi-interacting RNAs (piRNAs), long thought to be restricted to germline, have recently been discovered in neurons of Aplysia, with a role in the epigenetic regulation of gene expression underlying long-term memory. We here ask whether piwi/piRNAs are also expressed and have functional roles in the mammalian brain. Large-scale RNA sequencing and subsequent analysis of protein expression revealed the presence in brain of several piRNA biogenesis factors including a mouse piwi (Mili), as well as small RNAs, albeit at low levels, resembling conserved piRNAs in mouse testes [primarily LINE1 (long interspersed nuclear element1) retrotransposon-derived]. Despite the seeming low expression of these putative piRNAs, single-base pair CpG methylation analyses across the genome of Mili/piRNA-deficient (Mili-/- ) mice demonstrate that brain genomic DNA is preferentially hypomethylated within intergenic areas and LINE1 promoter areas of the genome. Furthermore, Mili mutant mice exhibit behavioral deficits such as hyperactivity and reduced anxiety. These results suggest that putative piRNAs exist in mammalian brain, and similar to the role of piRNAs in testes, they may be involved in the silencing of retrotransposons, which in brain have critical roles in contributing to genomic heterogeneity underlying adaptation, stress response, and brain pathology. We also describe the presence of another class of small RNAs in the brain, with features of endogenous siRNAs, which may have taken over the role of invertebrate piRNAs in their capacity to target both transposons, as well as protein-coding genes. Thus, RNA interference through gene and retrotransposon silencing previously encountered in Aplysia may also have potential roles in the mammalian brain.

5.
J Neurosci ; 37(20): 5144-5154, 2017 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-28438970

RESUMO

Attention-deficit/hyperactivity disorder (ADHD) and anxiety-related disorders occur at rates 2-3 times higher in deaf compared with hearing children. Potential explanations for these elevated rates and the heterogeneity of behavioral disorders associated with deafness have usually focused on socio-environmental rather than biological effects. Children with the 22q11.2 deletion or duplication syndromes often display hearing loss and behavioral disorders, including ADHD and anxiety-related disorders. Here, we show that mouse mutants with either a gain or loss of function of the T-Box transcription factor gene, Tbx1, which lies within the 22q11.2 region and is responsible for most of the syndromic defects, exhibit inner ear defects and hyperactivity. Furthermore, we show that (1) inner ear dysfunction due to the tissue-specific loss of Tbx1 or Slc12a2, which encodes a sodium-potassium-chloride cotransporter and is also necessary for inner ear function, causes hyperactivity; (2) vestibular rather than auditory failure causes hyperactivity; and (3) the severity rather than the age of onset of vestibular dysfunction differentiates whether hyperactivity or anxiety co-occurs with inner ear dysfunction. Together, these findings highlight a biological link between inner ear dysfunction and behavioral disorders and how sensory abnormalities can contribute to the etiology of disorders traditionally considered of cerebral origin.SIGNIFICANCE STATEMENT This study examines the biological rather than socio-environmental reasons why hyperactivity and anxiety disorders occur at higher rates in deaf individuals. Using conditional genetic approaches in mice, the authors show that (1) inner ear dysfunction due to either Tbx1 or Slc12a2 mutations cause hyperactivity; (2) it is vestibular dysfunction, which frequently co-occurs with deafness but often remains undiagnosed, rather than auditory dysfunction that causes hyperactivity and anxiety-related symptoms; and (3) the severity of vestibular dysfunction can predict whether hyperactivity or anxiety coexist with inner ear dysfunction. These findings suggest a need to evaluate vestibular function in hearing impaired individuals, especially those who exhibit hyperactive and anxiety-related symptoms.


Assuntos
Ansiedade/complicações , Ansiedade/fisiopatologia , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Comportamento Animal , Surdez/fisiopatologia , Doenças Vestibulares/fisiopatologia , Animais , Ansiedade/patologia , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Deficit de Atenção com Hiperatividade/patologia , Surdez/complicações , Surdez/patologia , Feminino , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Índice de Gravidade de Doença , Doenças Vestibulares/complicações , Doenças Vestibulares/patologia
6.
J Neurosci ; 37(23): 5690-5698, 2017 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-28483978

RESUMO

FGF signaling, an important component of intercellular communication, is required in many tissues throughout development to promote diverse cellular processes. Whether FGF receptors (FGFRs) accomplish such varied tasks in part by activating different intracellular transducers in different contexts remains unclear. Here, we used the developing mouse telencephalon as an example to study the role of the FRS adapters FRS2 and FRS3 in mediating the functions of FGFRs. Using tissue-specific and germline mutants, we examined the requirement of Frs genes in two FGFR-dependent processes. We found that Frs2 and Frs3 are together required for the differentiation of a subset of medial ganglionic eminence (MGE)-derived neurons, but are dispensable for the survival of early telencephalic precursor cells, in which any one of three FGFRs (FGFR1, FGFR2, or FGFR3) is sufficient for survival. Although FRS adapters are dispensable for ERK-1/2 activation, they are required for AKT activation within the subventricular zone of the developing MGE. Using an FRS2,3-binding site mutant of Fgfr1, we established that FRS adapters are necessary for mediating most or all FGFR1 signaling, not only in MGE differentiation, but also in cell survival, implying that other adapters mediate at least in part the signaling from FGFR2 and FGFR3. Our study provides an example of a contextual role for an intracellular transducer and contributes to our understanding of how FGF signaling plays diverse developmental roles.SIGNIFICANCE STATEMENT FGFs promote a range of developmental processes in many developing tissues and at multiple developmental stages. The mechanisms underlying this multifunctionality remain poorly defined in vivo Using telencephalon development as an example, we show here that FRS adapters exhibit some selectivity in their requirement for mediating FGF receptor (FGFR) signaling and activating downstream mediators that depend on the developmental process, with a requirement in neuronal differentiation but not cell survival. Differential engagement of FRS and non-FRS intracellular adapters downstream of FGFRs could therefore in principle explain how FGFs play several distinct roles in other developing tissues and developmental stages.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Células-Tronco Neurais/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Telencéfalo/embriologia , Telencéfalo/metabolismo , Animais , Sobrevivência Celular/fisiologia , Células Cultivadas , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Células-Tronco Neurais/citologia , Telencéfalo/citologia
7.
Hum Mol Genet ; 25(4): 755-65, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26681803

RESUMO

High levels of aneuploidy have been observed in disease-free tissues, including post-mitotic tissues such as the brain. Using a quantitative interphase-fluorescence in situ hybridization approach, we previously reported a chromosome-specific, age-related increase in aneuploidy in the mouse cerebral cortex. Increased aneuploidy has been associated with defects in DNA repair and the spindle assembly checkpoint, which in turn can lead to premature aging. Here, we quantified the frequency of aneuploidy of three autosomes in the cerebral cortex and cerebellum of adult and developing brain of Bub1b(H/H) mice, which have a faulty mitotic checkpoint, and Ercc1(-/Δ7) mice, defective in nucleotide excision repair and inter-strand cross-link repair. Surprisingly, the level of aneuploidy in the brain of these murine models of accelerated aging remains as low as in the young adult brains from control animals, i.e. <1% in the cerebral cortex and ∼0.1% in the cerebellum. Therefore, based on aneuploidy, these adult mice with reduced life span and accelerated progeroid features are indistinguishable from age-matched, normal controls. Yet, during embryonic development, we found that Bub1b(H/H), but not Ercc1(-/Δ7) mice, have a significantly higher frequency of aneuploid nuclei relative to wild-type controls in the cerebral cortex, reaching a frequency as high as 40.3% for each chromosome tested. Aneuploid cells in these mutant mice are likely eliminated early in development through apoptosis and/or immune-mediated clearance mechanisms, which would explain the low levels of aneuploidy during adulthood in the cerebral cortex of Bub1b(H/H) mice. These results shed light on the mechanisms of removal of aneuploidy cells in vivo.


Assuntos
Aneuploidia , Proteínas de Ciclo Celular/genética , Cerebelo/fisiologia , Córtex Cerebral/fisiologia , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Proteínas Serina-Treonina Quinases/genética , Fatores Etários , Senilidade Prematura/genética , Animais , Apoptose/genética , Pontos de Checagem do Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Cromossomos , Reparo do DNA , Proteínas de Ligação a DNA/metabolismo , Endonucleases/metabolismo , Hibridização in Situ Fluorescente , Masculino , Camundongos , Camundongos Knockout , Proteínas Serina-Treonina Quinases/metabolismo
8.
Proc Natl Acad Sci U S A ; 111(29): E2987-95, 2014 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-25002516

RESUMO

In the brain, astrocytes are multifunctional cells that react to insults and contain damage. However, excessive or sustained reactive astrocytes can be deleterious to functional recovery or contribute to chronic inflammation and neuronal dysfunction. Therefore, astrocyte activation in response to damage is likely to be tightly regulated. Although factors that activate astrocytes have been identified, whether factors also exist that maintain astrocytes as nonreactive or reestablish their nonreactive state after containing damage remains unclear. By using loss- and gain-of-function genetic approaches, we show that, in the unperturbed adult neocortex, FGF signaling is required in astrocytes to maintain their nonreactive state. Similarly, after injury, FGF signaling delays the response of astrocytes and accelerates their deactivation. In addition, disrupting astrocytic FGF receptors results in reduced scar size without affecting neuronal survival. Overall, this study reveals that the activation of astrocytes in the normal and injured neocortex is not only regulated by proinflammatory factors, but also by factors such as FGFs that suppress activation, providing alternative therapeutic targets.


Assuntos
Astrócitos/metabolismo , Astrócitos/patologia , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Animais , Córtex Cerebral/patologia , Cicatriz/metabolismo , Cicatriz/patologia , Genótipo , Proteína Glial Fibrilar Ácida/metabolismo , Gliose/metabolismo , Gliose/patologia , Camundongos , Neuroglia/metabolismo , Neuroglia/patologia , Células Piramidais/metabolismo , Células Piramidais/patologia , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo
9.
J Neurosci ; 35(28): 10217-23, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-26180198

RESUMO

The mechanisms regulating hippocampal neurogenesis remain poorly understood. Particularly unclear is the extent to which age-related declines in hippocampal neurogenesis are due to an innate decrease in precursor cell performance or to changes in the environment of these cells. Several extracellular signaling factors that regulate hippocampal neurogenesis have been identified. However, the role of one important family, FGFs, remains uncertain. Although a body of literature suggests that FGFs can promote the proliferation of cultured adult hippocampal precursor cells, their requirement for adult hippocampal neurogenesis in vivo and the cell types within the neurogenic lineage that might depend on FGFs remain unclear. Here, specifically targeting adult neural precursor cells, we conditionally express an activated form of an FGF receptor or delete the FGF receptors that are expressed in these cells. We find that FGF receptors are required for neural stem-cell maintenance and that an activated receptor expressed in all precursors can increase the number of neurons produced. Moreover, in older mice, an activated FGF receptor can rescue the age-related decline in neurogenesis to a level found in young adults. These results suggest that the decrease in neurogenesis with age is not simply due to fewer stem cells, but also to declining signals in their niche. Thus, enhancing FGF signaling in precursors can be used to reverse age-related declines in hippocampal neurogenesis. SIGNIFICANCE STATEMENT: Hippocampal deficits can result from trauma, neurodegeneration, or aging and can lead to loss of memory and mood control. The addition of new neurons to the hippocampus facilitates memory formation, but how this process is regulated and how we might manipulate it to reverse hippocampal dysfunction remains unclear. The FGF signaling pathway has been hypothesized to be important, but its role in generating new neurons had been poorly defined. Our study indicates that FGF signaling maintains and expands subsets of neural precursor cells. Moreover, in older mice, increasing FGF signaling is sufficient to reverse the decline in neuron production to levels found in young adults, providing a potential means of reversing age-related hippocampal deficits.


Assuntos
Envelhecimento/fisiologia , Fatores de Crescimento de Fibroblastos/metabolismo , Hipocampo/citologia , Neurogênese/fisiologia , Neurônios/fisiologia , Transdução de Sinais/fisiologia , Envelhecimento/genética , Animais , Contagem de Células , Proteínas do Domínio Duplacortina , Proteína Glial Fibrilar Ácida/metabolismo , Antígeno Ki-67/metabolismo , Camundongos , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/metabolismo , Nestina/genética , Nestina/metabolismo , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Células-Tronco Neurais/fisiologia , Neurogênese/genética , Neuropeptídeos/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Ácidos Siálicos/metabolismo
10.
J Neurosci ; 33(15): 6278-84, 2013 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-23575827

RESUMO

Adult neurogenesis is actively studied in part because of the potential to manipulate endogenous neural stem and progenitor cells for tissue repair. Although constitutive generation of neurons in the adult rodent olfactory bulb and hippocampal dentate gyrus is widely accepted and stroke-induced generation of striatal inhibitory neurons consistently observed, evidence supporting the generation of neurons in the neocortex after neuronal loss remains slim. Nevertheless, a few studies suggested that targeted apoptosis of neocortical glutamatergic neurons could trigger the generation of new ones in the adult brain. In light of such studies, we tested whether apoptosis of glutamatergic cortical neurons using two novel transgenic approaches in mice, an inducible Caspase-8 protein and an inducible diphtheria toxin gene, results in new neurons. After a thorough analysis, no new neurons were detected in the neocortex. Interestingly, an increase in the expression of the neuroblast marker DCX was observed in both models, in some cases in cells with morphologies previously associated with poststroke neuroblasts, but DCX(+) cells coexpressed the oligodendrocyte precursor marker Olig2, suggesting caution when using DCX as a marker for neuroblasts after injury. Given that the adult neocortex lacks an innate potential to regenerate lost glutamatergic neurons, future strategies should concentrate on manipulating the differentiation potential of endogenous or exogenous precursor cells.


Assuntos
Apoptose/fisiologia , Glutamatos/fisiologia , Neocórtex/fisiologia , Neurogênese/fisiologia , Neurônios/fisiologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Caspase 8/genética , Toxina Diftérica/genética , Proteínas do Domínio Duplacortina , Proteína Duplacortina , Camundongos , Camundongos Transgênicos , Microglia/metabolismo , Proteínas Associadas aos Microtúbulos/biossíntese , Degeneração Neural/genética , Degeneração Neural/metabolismo , Proteínas do Tecido Nervoso/biossíntese , Neuropeptídeos/biossíntese , Fator de Transcrição 2 de Oligodendrócitos , Regulação para Cima
11.
Dev Biol ; 365(1): 82-90, 2012 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-22370000

RESUMO

Cerebellum development involves the coordinated production of multiple neuronal cell types. The cerebellar primordium contains two germinative zones, the rhombic lip (RL) and the ventricular zone (VZ), which generate different types of glutamatergic and GABAergic neurons, respectively. What regulates the specification and production of glutamatergic and GABAergic neurons as well as the subtypes for each of these two broad classes remains largely unknown. Here we demonstrate with conditional genetic approaches in mice that SMAD4, a major mediator of BMP and TGFß signaling, is required early in cerebellar development for maintaining the RL and generating subsets of RL-derived glutamatergic neurons, namely neurons of the deep cerebellar nuclei, unipolar brush cells, and the late cohort of granule cell precursors (GCPs). The early cohort of GCPs, despite being deficient for SMAD4, is still generated. In addition, the numbers of GABAergic neurons are reduced in the mutant and the distribution of Purkinje cells becomes abnormal. These studies demonstrate a temporally and spatially restricted requirement for SMAD4 in generating subtypes of cerebellar neurons.


Assuntos
Cerebelo/citologia , Cerebelo/embriologia , Neurônios/citologia , Proteína Smad4/fisiologia , Animais , Diferenciação Celular , Núcleos Cerebelares/citologia , Núcleos Cerebelares/embriologia , Cerebelo/fisiologia , Camundongos , Neurônios/fisiologia , Células de Purkinje/citologia , Células de Purkinje/fisiologia , Fator de Crescimento Transformador beta/fisiologia
12.
Development ; 137(10): 1601-11, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20392740

RESUMO

The olfactory sensory epithelium and the respiratory epithelium are derived from the olfactory placode. However, the molecular mechanisms regulating the differential specification of the sensory and the respiratory epithelium have remained undefined. To address this issue, we first identified Msx1/2 and Id3 as markers for respiratory epithelial cells by performing quail chick transplantation studies. Next, we established chick explant and intact chick embryo assays of sensory/respiratory epithelial cell differentiation and analyzed two mice mutants deleted of Bmpr1a;Bmpr1b or Fgfr1;Fgfr2 in the olfactory placode. In this study, we provide evidence that in both chick and mouse, Bmp signals promote respiratory epithelial character, whereas Fgf signals are required for the generation of sensory epithelial cells. Moreover, olfactory placodal cells can switch between sensory and respiratory epithelial cell fates in response to Fgf and Bmp activity, respectively. Our results provide evidence that Fgf activity suppresses and restricts the ability of Bmp signals to induce respiratory cell fate in the nasal epithelium. In addition, we show that in both chick and mouse the lack of Bmp or Fgf activity results in disturbed placodal invagination; however, the fate of cells in the remaining olfactory epithelium is independent of morphological movements related to invagination. In summary, we present a conserved mechanism in amniotes in which Bmp and Fgf signals act in an opposing manner to regulate the respiratory versus sensory epithelial cell fate decision.


Assuntos
Proteínas Morfogenéticas Ósseas/farmacologia , Diferenciação Celular/efeitos dos fármacos , Fatores de Crescimento de Fibroblastos/farmacologia , Mucosa Olfatória/efeitos dos fármacos , Mucosa Respiratória/efeitos dos fármacos , Células Receptoras Sensoriais/efeitos dos fármacos , Animais , Proteínas Morfogenéticas Ósseas/antagonistas & inibidores , Proteínas Morfogenéticas Ósseas/metabolismo , Proteínas Morfogenéticas Ósseas/fisiologia , Células CHO , Diferenciação Celular/genética , Células Cultivadas , Embrião de Galinha , Cricetinae , Cricetulus , Antagonismo de Drogas , Embrião de Mamíferos , Embrião não Mamífero , Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Fatores de Crescimento de Fibroblastos/metabolismo , Fatores de Crescimento de Fibroblastos/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Camundongos , Modelos Biológicos , Mucosa Olfatória/metabolismo , Mucosa Olfatória/fisiologia , Condutos Olfatórios/efeitos dos fármacos , Condutos Olfatórios/metabolismo , Condutos Olfatórios/fisiologia , Codorniz/embriologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/fisiologia , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
13.
Dev Dyn ; 241(2): 242-6, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22102609

RESUMO

BACKGROUND: The early telencephalon shares molecular features with the early mid-hindbrain region. In particular, these two developing brain areas each have a signaling center that secretes FGFs and an adjacent one that secretes WNTs. WNTs and FGFs each play essential roles in regulating cell fates in both the telencephalon and mid-hindbrain. Despite this similarity, telencephalic and mid-hindbrain precursors express distinct genes and ultimately generate different cell types, tissue morphologies, and neural functions. RESULTS: Here we show that genetically increasing the level of ß-catenin, a mediator of canonical WNT signaling, in the anterior neural plate causes a loss of telencephalic characteristics and a gain of mid-hindbrain characteristics. CONCLUSION: These results, together with previous ones demonstrating that increased WNT signaling in the anterior neural plate increases FGF expression, suggest that the levels of WNT and FGF signaling regulate telencephalic versus mid-hindbrain fates.


Assuntos
Mesencéfalo/metabolismo , Placa Neural/metabolismo , Rombencéfalo/metabolismo , beta Catenina/metabolismo , Animais , Fatores de Crescimento de Fibroblastos/metabolismo , Mesencéfalo/embriologia , Camundongos , Camundongos Mutantes , Placa Neural/embriologia , Rombencéfalo/embriologia , Telencéfalo/embriologia , Telencéfalo/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/genética
14.
Bioengineering (Basel) ; 10(2)2023 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-36829757

RESUMO

Recent progress in cortical stem cell transplantation has demonstrated its potential to repair the brain. However, current transplant models have yet to demonstrate that the circuitry of transplant-derived neurons can encode useful function to the host. This is likely due to missing cell types within the grafts, abnormal proportions of cell types, abnormal cytoarchitecture, and inefficient vascularization. Here, we devised a transplant platform for testing neocortical tissue prototypes. Dissociated mouse embryonic telencephalic cells in a liquid scaffold were transplanted into aspiration-lesioned adult mouse cortices. The donor neuronal precursors differentiated into upper and deep layer neurons that exhibited synaptic puncta, projected outside of the graft to appropriate brain areas, became electrophysiologically active within one month post-transplant, and responded to visual stimuli. Interneurons and oligodendrocytes were present at normal densities in grafts. Grafts became fully vascularized by one week post-transplant and vessels in grafts were perfused with blood. With this paradigm, we could also organize cells into layers. Overall, we have provided proof of a concept for an in vivo platform that can be used for developing and testing neocortical-like tissue prototypes.

15.
J Neurosci ; 31(13): 5055-66, 2011 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-21451043

RESUMO

Fibroblast growth factors (FGFs) comprise a family of developmental regulators implicated in a wide variety of neurological functions. FGF receptors 1, 2, and 3 (Fgfrs) are expressed in the embryonic forebrain, including regions overlapping with ventral sites of oligodendrocyte progenitor (OLP) generation. Although FGF signaling is known to influence the proliferation of OLPs in vitro, functions of different Fgfrs in vivo are lacking. Here, we examined single and double mutants with conditional disruption of Fgfrs, specifically in the embryonic forebrain, to investigate the effect of FGFs on the generation and proliferation of OLPs in vivo. FGF signaling, through cooperation between Fgfr1 and Fgfr2 but not Fgfr3, is required for the initial generation of OLPs in the mouse ventral forebrain, with Fgfr1 being a stronger inducer than Fgfr2. In cultures derived from embryonic mutant forebrains or from normal forebrains grown in the presence of Fgfr inhibitor, a strong attenuation of OLP generation was observed, supporting the role of FGF signaling in vivo. Contrary to in vitro findings, Fgfr1 and Fgfr2 signaling is not required for the proliferation of OLPs in vivo. Finally, failure of OLP generation in the Fgfr mutants occurred without loss of sonic hedgehog (Shh) signaling; and pharmacological inhibition of either Fgfr or hedgehog signaling in parallel cultures strongly inhibited OLP generation, suggesting that Fgfrs cooperate with Shh to generate OLPs. Overall, our results reveal for the first time an essential role of FGF signaling in vivo, where the three Fgfrs differentially control the normal generation of OLPs from the embryonic ventral forebrain.


Assuntos
Células-Tronco Embrionárias/fisiologia , Neurogênese/genética , Oligodendroglia/fisiologia , Prosencéfalo/embriologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/fisiologia , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/fisiologia , Transdução de Sinais/genética , Animais , Células Cultivadas , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Fatores de Crescimento de Fibroblastos/fisiologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Oligodendroglia/citologia , Prosencéfalo/citologia , Prosencéfalo/fisiologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/deficiência , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/deficiência , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Células-Tronco/citologia , Células-Tronco/metabolismo , Células-Tronco/fisiologia
16.
Am J Med Genet A ; 158A(11): 2797-806, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22987770

RESUMO

Central nervous system anomalies in Pfeiffer syndrome (PS) due to mutations in the FGFR2 gene are poorly understood, even though PS is often associated with serious cognitive impairment. The aim of this study is to describe the neuropathological phenotype in PS. We present four severe fetal cases of sporadic PS with FGFR2 mutations who underwent termination followed by fetopathological and neuropathological examination. We studied the expression pattern of Fgfr2 in the mouse brain using radioactive fluorescence in situ hybridization. PS is associated with brain deformations due to the abnormal skull shape, but FGFR2 mutations also induce specific brain developmental anomalies: megalencephaly, midline disorders, amygdala, and hippocampus malformations, and ventricular wall alterations. The expression pattern of Fgfr2 in mice matches the distribution of malformations in humans. The brain anomalies in PS result from the combination of mechanical deformations and intrinsic developmental disorders due to FGFR2 hyperactivity. Several similarities are noted between these anomalies and the brain lesions observed in other syndromes due to mutations in FGF-receptor genes. The specific involvement of the hippocampus and the amygdala should encourage the precise cognitive screening of patients with mild forms of PS.


Assuntos
Encéfalo/anormalidades , Craniossinostoses/genética , Craniossinostoses/patologia , Mutação , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Feto Abortado , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Craniossinostoses/diagnóstico , Estudos de Associação Genética , Humanos , Camundongos , Fenótipo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo
17.
Cells ; 11(10)2022 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-35626693

RESUMO

Interest is growing in using cell replacements to repair the damage caused by an ischemic stroke. Yet, the usefulness of cell transplants can be limited by the variability observed in their successful engraftment. For example, we recently showed that, although the inclusion of donor-derived vascular cells was necessary for the formation of large grafts (up to 15 mm3) at stroke sites in mice, the size of the grafts overall remained highly variable. Such variability can be due to differences in the cells used for transplantation or the host environment. Here, as possible factors affecting engraftment, we test host sex, host age, the extent of ischemic damage, time of transplant after ischemia, minor differences in donor cell maturity, and cell viability at the time of transplantation. We find that graft size at stroke sites correlates with the size of ischemic damage, host sex (females having graft sizes that correlate with damage), donor cell maturity, and host age, but not with the time of transplant after stroke. A general linear model revealed that graft size is best predicted by stroke severity combined with donor cell maturity. These findings can serve as a guide to improving the reproducibility of cell-based repair therapies.


Assuntos
Acidente Vascular Cerebral , Animais , Feminino , Humanos , Isquemia , Camundongos , Neurônios , Reprodutibilidade dos Testes , Doadores de Tecidos
18.
Stem Cell Res ; 59: 102642, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34971934

RESUMO

Neural precursor cells (NPCs) transplanted into the adult neocortex generate neurons that synaptically integrate with host neurons, supporting the possibility of achieving functional tissue repair. However, poor survival and functional neuronal recovery of transplanted NPCs greatly limits engraftment. Here, we test the hypothesis that combining blood vessel-forming vascular cells with neuronal precursors improves engraftment. By transplanting mixed embryonic neocortical cells into adult mice with neocortical strokes, we show that transplant-derived neurons synapse with appropriate targets while donor vascular cells form vessels that fuse with the host vasculature to perfuse blood within the graft. Although all grafts became vascularized, larger grafts had greater contributions of donor-derived vessels that increased as a function of their distance from the host-graft border. Moreover, excluding vascular cells from the donor cell population strictly limited graft size. Thus, inclusion of vessel-forming vascular cells with NPCs is required for more efficient engraftment and ultimately for tissue repair.

19.
Neuroscience ; 453: 148-167, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33246055

RESUMO

Fibroblast Growth Factor Receptors (FGFRs) play crucial roles in promoting dendrite growth and branching during development. In mice, three FGFR genes, Fgfr1, Fgfr2, and Fgfr3, remain expressed in the adult neurogenic niche of the hippocampal dentate gyrus. However, the function of FGFRs in the dendritic maturation of adult-born neurons remains largely unexplored. Here, using conditional alleles of Fgfr1, Fgfr2, and Fgfr3 as well as Fgfr1 alleles lacking binding sites for Phospholipase-Cγ (PLCγ) and FGF Receptor Substrate (FRS) proteins, we test the requirement for FGFRs in dendritogenesis of adult-born granule cells. We find that deleting all three receptors results in a small decrease in proximal dendrite elaboration. In contrast, specifically mutating Tyr766 in FGFR1 (a PLCγ binding site) in an Fgfr2;Fgfr3 deficient background results in a dramatic increase of overall dendrite elaboration, while blocking FGFR1-FRS signaling causes proximal dendrite deficits and, to a lesser extent than Tyr766 mutants, increases distal dendrite elaboration. These findings reveal unexpectedly complex roles for FGFRs and their intracellular mediators in regulating proximal and distal dendrite elaboration, with the most notable role in suppressing distal elaboration through the PLCγbinding site.


Assuntos
Dendritos , Neurônios , Receptores de Fatores de Crescimento de Fibroblastos/genética , Transdução de Sinais , Animais , Dendritos/metabolismo , Camundongos , Neurogênese , Neurônios/metabolismo , Fosforilação , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo
20.
Transl Oncol ; 14(8): 101114, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33975179

RESUMO

Across many cancer types in adults, upregulation of the nuclear-to-cytoplasmic transport protein Exportin-1 (XPO1) correlates with poor outcome and responsiveness to selinexor, an FDA-approved XPO1 inhibitor. Similar data are emerging in childhood cancers, for which selinexor is being evaluated in early phase clinical studies. Using proteomic profiling of primary tumor material from patients with high-risk neuroblastoma, as well as gene expression profiling from independent cohorts, we have demonstrated that XPO1 overexpression correlates with poor patient prognosis. Neuroblastoma cell lines are also sensitive to selinexor in the low nanomolar range. Based on these findings and knowledge that bortezomib, a proteasome inhibitor, blocks degradation of XPO1 cargo proteins, we hypothesized that combination treatment with selinexor and bortezomib would synergistically inhibit neuroblastoma cellular proliferation. We observed that selinexor promoted nuclear retention of IkB and that bortezomib augmented the ability of selinexor to induce cell-cycle arrest and cell death by apoptosis. This synergy was abrogated through siRNA knockdown of IkB. The synergistic effect of combining selinexor and bortezomib in vitro provides rationale for further investigation of this combination treatment for patients with high-risk neuroblastoma.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA