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1.
Am J Med Genet A ; 194(6): e63528, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38169111

RESUMO

Somatic variants in the NOTCH pathway regulator FBXW7 are frequently seen in a variety of malignancies. Heterozygous loss-of-function germline variants in FBXW7 have recently been described as causative for a neurodevelopmental syndrome. Independently, FBXW7 was also considered as a susceptibility gene for Wilms tumor due to a few observations of heterozygous germline variants in patients with Wilms tumor. Whether the same FBXW7 variants are implicated in both, neurodevelopmental delay and Wilms tumor formation, remained unclear. By clinical testing, we now observed a patient with neurodevelopmental delay due to a de novo constitutional mosaic FBXW7 splice site pathogenic variant who developed Wilms tumor. In the tumor, we identified a second hit frameshift variant in FBXW7. Immunohistochemical staining was consistent with mosaic loss of FBXW7 protein expression in the tumor. Our data support the role of constitutional FBXW7 pathogenic variants in both, neurodevelopmental disorder and the etiology of Wilms tumor. Therefore, Wilms tumor screening should be considered in individuals with constitutional or germline pathogenic variants in FBXW7 and associated neurodevelopmental syndrome.


Assuntos
Proteína 7 com Repetições F-Box-WD , Predisposição Genética para Doença , Tumor de Wilms , Humanos , Masculino , Proteína 7 com Repetições F-Box-WD/genética , Mutação da Fase de Leitura/genética , Mutação em Linhagem Germinativa/genética , Neoplasias Renais/genética , Neoplasias Renais/patologia , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Tumor de Wilms/genética , Tumor de Wilms/patologia , Criança
2.
Plant Physiol ; 158(1): 225-38, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22045922

RESUMO

The function of PsBRC1, the pea (Pisum sativum) homolog of the maize (Zea mays) TEOSINTE BRANCHED1 and the Arabidopsis (Arabidopsis thaliana) BRANCHED1 (AtBRC1) genes, was investigated. The pea Psbrc1 mutant displays an increased shoot-branching phenotype, is able to synthesize strigolactone (SL), and does not respond to SL application. The level of pleiotropy of the SL-deficient ramosus1 (rms1) mutant is higher than in the Psbrc1 mutant, rms1 exhibiting a relatively dwarf phenotype and more extensive branching at upper nodes. The PsBRC1 gene is mostly expressed in the axillary bud and is transcriptionally up-regulated by direct application of the synthetic SL GR24 and down-regulated by the cytokinin (CK) 6-benzylaminopurine. The results suggest that PsBRC1 may have a role in integrating SL and CK signals and that SLs act directly within the bud to regulate its outgrowth. However, the Psbrc1 mutant responds to 6-benzylaminopurine application and decapitation by increasing axillary bud length, implicating a PsBRC1-independent component of the CK response in sustained bud growth. In contrast to other SL-related mutants, the Psbrc1 mutation does not cause a decrease in the CK zeatin riboside in the xylem sap or a strong increase in RMS1 transcript levels, suggesting that the RMS2-dependent feedback is not activated in this mutant. Surprisingly, the double rms1 Psbrc1 mutant displays a strong increase in numbers of branches at cotyledonary nodes, whereas branching at upper nodes is not significantly higher than the branching in rms1. This phenotype indicates a localized regulation of branching at these nodes specific to pea.


Assuntos
Lactonas/metabolismo , Pisum sativum/crescimento & desenvolvimento , Brotos de Planta/crescimento & desenvolvimento , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas de Arabidopsis/metabolismo , Compostos de Benzil , Citocininas/genética , Citocininas/metabolismo , Regulação da Expressão Gênica de Plantas , Isopenteniladenosina/análogos & derivados , Isopenteniladenosina/metabolismo , Cinetina/farmacologia , Dados de Sequência Molecular , Mutação , Pisum sativum/efeitos dos fármacos , Pisum sativum/genética , Pisum sativum/metabolismo , Reguladores de Crescimento de Plantas/farmacologia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Brotos de Planta/genética , Brotos de Planta/metabolismo , Purinas , Transdução de Sinais/genética , Regulação para Cima , Xilema/genética , Xilema/metabolismo
3.
Transl Psychiatry ; 13(1): 143, 2023 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-37137886

RESUMO

FIP200 plays important roles in homeostatic processes such as autophagy and signaling pathways such as focal adhesion kinase (FAK) signaling. Furthermore, genetic studies suggest an association of FIP200 mutations with psychiatric disorders. However, its potential connections to psychiatric disorders and specific roles in human neurons are not clear. We set out to establish a human-specific model to study the functional consequences of neuronal FIP200 deficiency. To this end, we generated two independent sets of isogenic human pluripotent stem cell lines with homozygous FIP200KO alleles, which were then used for the derivation of glutamatergic neurons via forced expression of NGN2. FIP200KO neurons exhibited pathological axonal swellings, showed autophagy deficiency, and subsequently elevated p62 protein levels. Moreover, monitoring the electrophysiological activity of neuronal cultures on multi-electrode arrays revealed that FIP200KO resulted in a hyperactive network. This hyperactivity could be abolished by glutamatergic receptor antagonist CNQX, suggesting a strengthened glutamatergic synaptic activation in FIP200KO neurons. Furthermore, cell surface proteomic analysis revealed metabolic dysregulation and abnormal cell adhesion-related processes in FIP200KO neurons. Interestingly, an ULK1/2-specific autophagy inhibitor could recapitulate axonal swellings and hyperactivity in wild-type neurons, whereas inhibition of FAK signaling was able to normalize the hyperactivity of FIP200KO neurons. These results suggest that impaired autophagy and presumably also disinhibition of FAK can contribute to the hyperactivity of FIP200KO neuronal networks, whereas pathological axonal swellings are primarily due to autophagy deficiency. Taken together, our study reveals the consequences of FIP200 deficiency in induced human glutamatergic neurons, which might, in the end, help to understand cellular pathomechanisms contributing to neuropsychiatric conditions.


Assuntos
Células-Tronco Pluripotentes , Proteômica , Humanos , Proteínas Relacionadas à Autofagia , Axônios/patologia , Neurônios
4.
Nat Commun ; 8: 14162, 2017 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-28102196

RESUMO

While transplantation represents a key tool for assessing in vivo functionality of neural stem cells and their suitability for neural repair, little is known about the integration of grafted neurons into the host brain circuitry. Rabies virus-based retrograde tracing has developed into a powerful approach for visualizing synaptically connected neurons. Here, we combine this technique with light sheet fluorescence microscopy (LSFM) to visualize transplanted cells and connected host neurons in whole-mouse brain preparations. Combined with co-registration of high-precision three-dimensional magnetic resonance imaging (3D MRI) reference data sets, this approach enables precise anatomical allocation of the host input neurons. Our data show that the same neural donor cell population grafted into different brain regions receives highly orthotopic input. These findings indicate that transplant connectivity is largely dictated by the circuitry of the target region and depict rabies-based transsynaptic tracing and LSFM as efficient tools for comprehensive assessment of host-donor cell innervation.


Assuntos
Mapeamento Encefálico , Células-Tronco Neurais/fisiologia , Neurônios/transplante , Animais , Encéfalo , Diferenciação Celular/fisiologia , Vetores Genéticos , Humanos , Interneurônios , Imageamento por Ressonância Magnética/métodos , Camundongos , Microscopia de Fluorescência/métodos , Neurônios/fisiologia , Vírus da Raiva/fisiologia
5.
Stem Cell Reports ; 7(2): 207-19, 2016 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-27426040

RESUMO

Tight regulation of the balance between self-renewal and differentiation of neural stem cells is crucial to assure proper neural development. In this context, Notch signaling is a well-known promoter of stemness. In contrast, the bifunctional brain-enriched microRNA miR-9/9(∗) has been implicated in promoting neuronal differentiation. Therefore, we set out to explore the role of both regulators in human neural stem cells. We found that miR-9/9(∗) decreases Notch activity by targeting NOTCH2 and HES1, resulting in an enhanced differentiation. Vice versa, expression levels of miR-9/9(∗) depend on the activation status of Notch signaling. While Notch inhibits differentiation of neural stem cells, it also induces miR-9/9(∗) via recruitment of the Notch intracellular domain (NICD)/RBPj transcriptional complex to the miR-9/9(∗)_2 genomic locus. Thus, our data reveal a mutual interaction between bifunctional miR-9/9(∗) and the Notch signaling cascade, calibrating the delicate balance between self-renewal and differentiation of human neural stem cells.


Assuntos
Diferenciação Celular/genética , Autorrenovação Celular/genética , MicroRNAs/genética , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Receptores Notch/metabolismo , Transcrição Gênica , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Regulação da Expressão Gênica , Loci Gênicos , Células-Tronco Embrionárias Humanas/citologia , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , MicroRNAs/metabolismo , Complexos Multiproteicos/metabolismo , Ligação Proteica , Transdução de Sinais/genética
6.
Biol Aujourdhui ; 204(1): 43-9, 2010.
Artigo em Francês | MEDLINE | ID: mdl-20950574

RESUMO

Plant architecture is a major trait for plant survival and plant fitness and has a huge influence on the agronomical value for most crops. The classical theory of apical dominance based on decapitation experiments suggested that two major plant hormones, auxin and cytokinins, were acting antagonistically on bud outgrowth to promote or repress branching. However this theory was challenged in the late 1930's by Snow who suggested the existence of a second messenger to auxin, as auxin was not acting directly to repress branching. The use of branching mutants in pea, Arabidopsis and rice led to the discovery of a new carotenoid-derived signal repressing branching. Genes involved in synthesis (RMS1, RMS5) as well as in response (RMS4) to this new signal have been identified and have given rise to a new model of the branching control. Two independent group have recently shown, one on pea, the other on rice, that strigolactones correspond to this novel signal which represses branching and to the secondary messenger in the theory of apical dominance. Strigolactones have been first identified for their role in germination of parasitic plants like Striga or Orobanche. They also play a critical role in the widespread association between 80% of plants and fungi, the arbuscular mycorrhizal symbiosis, as they are necessary for interaction between certain plants and fungi in the rhizosphere.


Assuntos
Reguladores de Crescimento de Plantas/fisiologia , Arabidopsis/genética , Arabidopsis/crescimento & desenvolvimento , Arabidopsis/fisiologia , Carotenoides/antagonistas & inibidores , Carotenoides/fisiologia , Homeostase , Lactonas/classificação , Oryza/genética , Oryza/crescimento & desenvolvimento , Oryza/fisiologia , Pisum sativum/genética , Pisum sativum/crescimento & desenvolvimento , Pisum sativum/fisiologia , Reguladores de Crescimento de Plantas/classificação , Transdução de Sinais
7.
PLoS One ; 4(9): e6648, 2009 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-19777056

RESUMO

BACKGROUND: In plants, the phytohormone auxin is a crucial regulator sustaining growth and development. At the cellular level, auxin is interpreted differentially in a tissue- and dose-dependent manner. Mechanisms of auxin signalling are partially unknown and the contribution of the AUXIN BINDING PROTEIN 1 (ABP1) as an auxin receptor is still a matter of debate. METHODOLOGY/PRINCIPAL FINDINGS: Here we took advantage of the present knowledge of the root biological system to demonstrate that ABP1 is required for auxin response. The use of conditional ABP1 defective plants reveals that the protein is essential for maintenance of the root meristem and acts at least on the D-type CYCLIN/RETINOBLASTOMA pathway to control entry into the cell cycle. ABP1 affects PLETHORA gradients and confers auxin sensitivity to root cells thus defining the competence of the cells to be maintained within the meristem or to elongate. ABP1 is also implicated in the regulation of gene expression in response to auxin. CONCLUSIONS/SIGNIFICANCE: Our data support that ABP1 is a key regulator for root growth and is required for auxin-mediated responses. Differential effects of ABP1 on various auxin responses support a model in which ABP1 is the major regulator for auxin action on the cell cycle and regulates auxin-mediated gene expression and cell elongation in addition to the already well known TIR1-mediated ubiquitination pathway.


Assuntos
Regulação da Expressão Gênica de Plantas , Ácidos Indolacéticos/metabolismo , Meristema/fisiologia , Proteínas de Plantas/fisiologia , Receptores de Superfície Celular/fisiologia , Arabidopsis/genética , Ciclo Celular , Crescimento Celular , Perfilação da Expressão Gênica , Cinética , Modelos Biológicos , Modelos Genéticos , Reguladores de Crescimento de Plantas/metabolismo , Reguladores de Crescimento de Plantas/fisiologia , Fenômenos Fisiológicos Vegetais , Raízes de Plantas/metabolismo , Ligação Proteica
8.
Plant Cell ; 20(10): 2746-62, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18952781

RESUMO

AUXIN BINDING PROTEIN1 (ABP1) has long been characterized as a potentially important mediator of auxin action in plants. Analysis of the functional requirement for ABP1 during development was hampered because of embryo lethality of the null mutant in Arabidopsis thaliana. Here, we used conditional repression of ABP1 to investigate its function during vegetative shoot development. Using an inducible cellular immunization approach and an inducible antisense construct, we showed that decreased ABP1 activity leads to a severe retardation of leaf growth involving an alteration in cell division frequency, an altered pattern of endocycle induction, a decrease in cell expansion, and a change in expression of early auxin responsive genes. In addition, local repression of ABP1 activity in the shoot apical meristem revealed an additional role for ABP1 in cell plate formation and cell shape. Moreover, cells at the site of presumptive leaf initiation were more sensitive to ABP1 repression than other regions of the meristem. This spatial context-dependent response of the meristem to ABP1 inactivation and the other data presented here are consistent with a model in which ABP1 acts as a coordinator of cell division and expansion, with local auxin levels influencing ABP1 effectiveness.


Assuntos
Proteínas de Arabidopsis/fisiologia , Arabidopsis/citologia , Divisão Celular/genética , Crescimento Celular , Nicotiana/citologia , Proteínas de Plantas/fisiologia , Brotos de Planta/crescimento & desenvolvimento , Receptores de Superfície Celular/fisiologia , Arabidopsis/genética , Arabidopsis/crescimento & desenvolvimento , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Etanol/farmacologia , Regulação da Expressão Gênica no Desenvolvimento , Ácidos Indolacéticos/farmacologia , Meristema/citologia , Meristema/crescimento & desenvolvimento , Meristema/metabolismo , Reguladores de Crescimento de Plantas/farmacologia , Folhas de Planta/citologia , Folhas de Planta/genética , Folhas de Planta/crescimento & desenvolvimento , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Brotos de Planta/citologia , Brotos de Planta/genética , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Transdução de Sinais , Nicotiana/genética , Nicotiana/crescimento & desenvolvimento
9.
Plant J ; 50(2): 197-206, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17376160

RESUMO

The phytohormone auxin has been known for >50 years to be required for entry into the cell cycle. Despite the critical effects exerted by auxin on the control of cell division, the molecular mechanism by which auxin controls this pathway is poorly understood, and how auxin is perceived upstream of any change in the cell cycle is unknown. Auxin Binding Protein 1 (ABP1) is considered to be a candidate auxin receptor, triggering early modification of ion fluxes across the plasma membrane in response to auxin. ABP1 has also been proposed to mediate auxin-dependent cell expansion, and is essential for early embryonic development. We investigated whether ABP1 has a role in the cell cycle. Functional inactivation of ABP1 in the model plant cell system BY2 was achieved through cellular immunization via the conditional expression of a single-chain fragment variable (scFv). This scFv was derived from a well characterized anti-ABP1 monoclonal antibody previously shown to block the activity of the protein. We demonstrate that functional inactivation of ABP1 results in cell-cycle arrest, and provide evidence that ABP1 plays a critical role in regulation of the cell cycle by acting at both the G1/S and G2/M checkpoints. We conclude that ABP1 is essential for the auxin control of cell division and is likely to constitute the first step of the auxin-signalling pathway mediating auxin effects on the cell cycle.


Assuntos
Ciclo Celular/fisiologia , Proteínas de Plantas/fisiologia , Receptores de Superfície Celular/fisiologia , Animais , Divisão Celular/fisiologia , Células Cultivadas , Citometria de Fluxo , Fase G1/fisiologia , Fase G2/fisiologia , Região Variável de Imunoglobulina/genética , Região Variável de Imunoglobulina/imunologia , Região Variável de Imunoglobulina/metabolismo , Imunoprecipitação , Camundongos , Proteínas de Plantas/imunologia , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas , Ligação Proteica , Receptores de Superfície Celular/imunologia , Receptores de Superfície Celular/metabolismo , Ressonância de Plasmônio de Superfície , Nicotiana/citologia , Nicotiana/genética , Nicotiana/metabolismo
10.
Proc Natl Acad Sci U S A ; 104(36): 14537-42, 2007 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-17726100

RESUMO

Current understanding of the integration of cell division and expansion in the development of plant lateral organs such as leaves is limited. Cell number is established during a mitotic phase, and subsequent growth into a mature organ relies primarily on cell expansion accompanied by endocycles. Here we show that the three Arabidopsis cyclin D3 (CYCD3) genes are expressed in overlapping but distinct patterns in developing lateral organs and the shoot meristem. Triple loss-of-function mutants show that CYCD3 function is essential neither for the mitotic cell cycle nor for morphogenesis. Rather, analysis of mutant and reciprocal overexpression phenotypes shows that CYCD3 function contributes to the control of cell number in developing leaves by regulating the duration of the mitotic phase and timing of the transition to endocycles. Petals, which normally do not endoreduplicate, respond to loss of CYCD3 function with larger cells that initiate endocycles. The phytohormone cytokinin regulates cell division in the shoot meristem and developing leaves and induces CYCD3 expression. Loss of CYCD3 impairs shoot meristem function and leads to reduced cytokinin responses, including the inability to initiate shoots on callus, without affecting endogenous cytokinin levels. We conclude that CYCD3 activity is important for determining cell number in developing lateral organs and the relative contribution of the alternative processes of cell production and cell expansion to overall organ growth, as well as mediating cytokinin effects in apical growth and development.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/citologia , Arabidopsis/metabolismo , Ciclinas/metabolismo , Citocininas/metabolismo , Envelhecimento/fisiologia , Arabidopsis/genética , Arabidopsis/crescimento & desenvolvimento , Proteínas de Arabidopsis/classificação , Proteínas de Arabidopsis/genética , Ciclo Celular , Proliferação de Células , Tamanho Celular , Ciclinas/classificação , Ciclinas/deficiência , Ciclinas/genética , Flores/genética , Flores/crescimento & desenvolvimento , Flores/metabolismo , Deleção de Genes , Regulação da Expressão Gênica de Plantas , Mutação/genética , Folhas de Planta/genética , Folhas de Planta/crescimento & desenvolvimento , Folhas de Planta/metabolismo , Brotos de Planta/genética , Brotos de Planta/metabolismo , Plantas Geneticamente Modificadas
11.
Acta Crystallogr B ; 61(Pt 2): 174-84, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15772450

RESUMO

A set of 112 993 structures was analysed for a specific type of packing: Molecular structures for which the centres of molecules form layers of centred hexagons exceed a percentage of 30%. This result has been obtained by a newly developed algorithm, allowing the extraction of these structures automatically and showing correlations between molecular shape and the type of packing.

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