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1.
Elife ; 132024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38722021

RESUMO

Neural stem cells (NSCs) are multipotent and correct fate determination is crucial to guarantee brain formation and homeostasis. How NSCs are instructed to generate neuronal or glial progeny is not well understood. Here, we addressed how murine adult hippocampal NSC fate is regulated and described how scaffold attachment factor B (SAFB) blocks oligodendrocyte production to enable neuron generation. We found that SAFB prevents NSC expression of the transcription factor nuclear factor I/B (NFIB) by binding to sequences in the Nfib mRNA and enhancing Drosha-dependent cleavage of the transcripts. We show that increasing SAFB expression prevents oligodendrocyte production by multipotent adult NSCs, and conditional deletion of Safb increases NFIB expression and oligodendrocyte formation in the adult hippocampus. Our results provide novel insights into a mechanism that controls Drosha functions for selective regulation of NSC fate by modulating the post-transcriptional destabilization of Nfib mRNA in a lineage-specific manner.


Assuntos
Hipocampo , Fatores de Transcrição NFI , Células-Tronco Neurais , Proteínas Associadas à Matriz Nuclear , RNA Mensageiro , Animais , Camundongos , Diferenciação Celular , Hipocampo/metabolismo , Hipocampo/citologia , Células-Tronco Neurais/metabolismo , Fatores de Transcrição NFI/metabolismo , Fatores de Transcrição NFI/genética , Proteínas Associadas à Matriz Nuclear/metabolismo , Oligodendroglia/metabolismo , Ribonuclease III/metabolismo , Ribonuclease III/genética , Estabilidade de RNA , RNA Mensageiro/metabolismo , RNA Mensageiro/genética
2.
Cereb Cortex ; 30(6): 3731-3743, 2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32080705

RESUMO

Neuronal activity initiates transcriptional programs that shape long-term changes in plasticity. Although neuron subtypes differ in their plasticity response, most activity-dependent transcription factors (TFs) are broadly expressed across neuron subtypes and brain regions. Thus, how region- and neuronal subtype-specific plasticity are established on the transcriptional level remains poorly understood. We report that in young adult (i.e., 6-8 weeks old) mice, the developmental TF SOX11 is induced in neurons within 6 h either by electroconvulsive stimulation or by exploration of a novel environment. Strikingly, SOX11 induction was restricted to the dentate gyrus (DG) of the hippocampus. In the novel environment paradigm, SOX11 was observed in a subset of c-FOS expressing neurons (ca. 15%); whereas around 75% of SOX11+ DG granule neurons were c-FOS+, indicating that SOX11 was induced in an activity-dependent fashion in a subset of neurons. Environmental enrichment or virus-mediated overexpression of SOX11 enhanced the excitability of DG granule cells and downregulated the expression of different potassium channel subunits, whereas conditional Sox11/4 knock-out mice presented the opposite phenotype. We propose that Sox11 is regulated in an activity-dependent fashion, which is specific to the DG, and speculate that activity-dependent Sox11 expression may participate in the modulation of DG neuron plasticity.


Assuntos
Giro Denteado/metabolismo , Comportamento Exploratório/fisiologia , Regulação da Expressão Gênica , Plasticidade Neuronal/genética , Neurônios/metabolismo , Fatores de Transcrição SOXC/genética , Animais , Eletrochoque , Camundongos , Camundongos Knockout , Técnicas de Patch-Clamp , Proteínas Proto-Oncogênicas c-fos/metabolismo , Fatores de Transcrição SOXC/metabolismo
3.
Sci Rep ; 8(1): 16196, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30385877

RESUMO

The intellectual disability gene, Sox11, encodes for a critical neurodevelopmental transcription factor with functions in precursor survival, neuronal fate determination, migration and morphogenesis. The mechanisms regulating SOX11's activity remain largely unknown. Mass spectrometric analysis uncovered that SOX11 can be post-translationally modified by phosphorylation. Here, we report that phosphorylatable serines surrounding the high-mobility group box modulate SOX11's transcriptional activity. Through Mass Spectrometry (MS), co-immunoprecipitation assays and in vitro phosphorylation assays followed by MS we verified that protein kinase A (PKA) interacts with SOX11 and phosphorylates it on S133. In vivo replacement of SoxC factors in developing adult-generated hippocampal neurons with SOX11 S133 phospho-mutants indicated that phosphorylation on S133 modulates dendrite development of adult-born dentate granule neurons, while reporter assays suggested that S133 phosphorylation fine-tunes the activation of select target genes. These data provide novel insight into the control of the critical neurodevelopmental regulator SOX11 and imply SOX11 as a mediator of PKA-regulated neuronal development.


Assuntos
Morfogênese/genética , Neurogênese/genética , Neurônios/metabolismo , Fatores de Transcrição SOXC/genética , Animais , Núcleos Cerebelares/crescimento & desenvolvimento , Núcleos Cerebelares/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/química , Proteínas Quinases Dependentes de AMP Cíclico/genética , Dendritos/genética , Dendritos/metabolismo , Hipocampo/crescimento & desenvolvimento , Hipocampo/metabolismo , Espectrometria de Massas , Camundongos , Fosforilação/genética , Serina/genética
4.
Neuron ; 99(6): 1188-1203.e6, 2018 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-30197237

RESUMO

Autophagy is a conserved catabolic pathway with emerging functions in mammalian neurodevelopment and human neurodevelopmental diseases. The mechanisms controlling autophagy in neuronal development are not fully understood. Here, we found that conditional deletion of the Forkhead Box O transcription factors FoxO1, FoxO3, and FoxO4 strongly impaired autophagic flux in developing neurons of the adult mouse hippocampus. Moreover, FoxO deficiency led to altered dendritic morphology, increased spine density, and aberrant spine positioning in adult-generated neurons. Strikingly, pharmacological induction of autophagy was sufficient to correct abnormal dendrite and spine development of FoxO-deficient neurons. Collectively, these findings reveal a novel link between FoxO transcription factors, autophagic flux, and maturation of developing neurons.


Assuntos
Autofagia/fisiologia , Fatores de Transcrição Forkhead/metabolismo , Morfogênese/fisiologia , Neurogênese/fisiologia , Animais , Separação Celular/métodos , Células Cultivadas , Camundongos Transgênicos , Neurônios/metabolismo
5.
Front Mol Neurosci ; 11: 211, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29973868

RESUMO

SOX11 is a key Transcription Factor (TF) in the regulation of embryonic and adult neurogenesis, whose mutation has recently been linked to an intellectual disability syndrome in humans. SOX11's transient activity during neurogenesis is critical to ensure the precise execution of the neurogenic program. Here, we report that SOX11 displays differential subcellular localizations during the course of neurogenesis. Western-Blot analysis of embryonic mouse brain lysates indicated that SOX11 is post-translationally modified by phosphorylation. Using Mass Spectrometry, we found 10 serine residues in the SOX11 protein that are putatively phosphorylated. Systematic analysis of phospho-mutant SOX11 resulted in the identification of the S30 residue, whose phosphorylation promotes nuclear over cytoplasmic localization of SOX11. Collectively, these findings uncover phosphorylation as a novel layer of regulation of the intellectual disability gene Sox11.

6.
J Neurochem ; 146(3): 251-268, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29749639

RESUMO

The high-mobility-group domain containing SoxC transcription factors Sox4 and Sox11 are expressed and required in the vertebrate central nervous system in neuronal precursors and neuroblasts. To identify genes that are widely regulated by SoxC proteins during vertebrate neurogenesis we generated expression profiles from developing mouse brain and chicken neural tube with reduced SoxC expression and found the transcription factor prospero homeobox protein 1 (Prox1) strongly down-regulated under both conditions. This led us to hypothesize that Prox1 expression depends on SoxC proteins in the developing central nervous system of mouse and chicken. By combining luciferase reporter assays and over-expression in the chicken neural tube with in vivo and in vitro binding studies, we identify the Prox1 gene promoter and two upstream enhancers at -44 kb and -40 kb relative to the transcription start as regulatory regions that are bound and activated by SoxC proteins. This argues that Prox1 is a direct target gene of SoxC proteins during neurogenesis. Electroporations in the chicken neural tube furthermore show that Prox1 activates a subset of SoxC target genes, whereas it has no effects on others. We propose that the transcriptional control of Prox1 by SoxC proteins may ensure coupling of two types of transcription factors that are both required during early neurogenesis, but have at least in part distinct functions. Open Data: Materials are available on https://cos.io/our-services/open-science-badges/ https://osf.io/93n6m/.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Proteínas de Homeodomínio/metabolismo , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Prosencéfalo/citologia , Fatores de Transcrição SOXC/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Embrião de Galinha , Imunoprecipitação da Cromatina , Biologia Computacional , Ensaio de Desvio de Mobilidade Eletroforética , Eletroporação , Embrião de Mamíferos , Ontologia Genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Proteínas de Homeodomínio/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Tubo Neural/citologia , Tubo Neural/metabolismo , Fatores do Domínio POU/genética , Fatores do Domínio POU/metabolismo , Prosencéfalo/embriologia , Prosencéfalo/crescimento & desenvolvimento , Prosencéfalo/metabolismo , Fatores de Transcrição SOXC/genética , Tubulina (Proteína)/metabolismo , Proteínas Supressoras de Tumor/genética
7.
Mol Autism ; 9: 20, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29588831

RESUMO

Background: Haploinsufficiency of the class I bHLH transcription factor TCF4 causes Pitt-Hopkins syndrome (PTHS), a severe neurodevelopmental disorder, while common variants in the TCF4 gene have been identified as susceptibility factors for schizophrenia. It remains largely unknown, which brain regions are dependent on TCF4 for their development and function. Methods: We systematically analyzed the expression pattern of TCF4 in the developing and adult mouse brain. We used immunofluorescent staining to identify candidate regions whose development and function depend on TCF4. In addition, we determined TCF4 expression in the developing rhesus monkey brain and in the developing and adult human brain through analysis of transcriptomic datasets and compared the expression pattern between species. Finally, we morphometrically and histologically analyzed selected brain structures in Tcf4-haploinsufficient mice and compared our morphometric findings to neuroanatomical findings in PTHS patients. Results: TCF4 is broadly expressed in cortical and subcortical structures in the developing and adult mouse brain. The TCF4 expression pattern was highly similar between humans, rhesus monkeys, and mice. Moreover, Tcf4 haploinsufficiency in mice replicated structural brain anomalies observed in PTHS patients. Conclusion: Our data suggests that TCF4 is involved in the development and function of multiple brain regions and indicates that its regulation is evolutionary conserved. Moreover, our data validate Tcf4-haploinsufficient mice as a model to study the neurodevelopmental basis of PTHS.


Assuntos
Córtex Cerebral/metabolismo , Haploinsuficiência , Hipocampo/metabolismo , Hiperventilação/genética , Deficiência Intelectual/genética , Esquizofrenia/genética , Fator de Transcrição 4/genética , Animais , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/crescimento & desenvolvimento , Criança , Fácies , Feminino , Hipocampo/citologia , Hipocampo/crescimento & desenvolvimento , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal , Neurônios/metabolismo , Neurônios/fisiologia , Fator de Transcrição 4/metabolismo
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