Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 18 de 18
Filtrar
1.
Development ; 148(3)2021 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-33462115

RESUMO

Fine-tuned gene expression is crucial for neurodevelopment. The gene expression program is tightly controlled at different levels, including RNA decay. N6-methyladenosine (m6A) methylation-mediated degradation of RNA is essential for brain development. However, m6A methylation impacts not only RNA stability, but also other RNA metabolism processes. How RNA decay contributes to brain development is largely unknown. Here, we show that Exosc10, a RNA exonuclease subunit of the RNA exosome complex, is indispensable for forebrain development. We report that cortical cells undergo overt apoptosis, culminating in cortical agenesis upon conditional deletion of Exosc10 in mouse cortex. Mechanistically, Exosc10 directly binds and degrades transcripts of the P53 signaling-related genes, such as Aen and Bbc3. Overall, our findings suggest a crucial role for Exosc10 in suppressing the P53 pathway, in which the rapid turnover of the apoptosis effectors Aen and Bbc3 mRNAs is essential for cell survival and normal cortical histogenesis.


Assuntos
Sobrevivência Celular/fisiologia , Exossomos/genética , Exossomos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Prosencéfalo/crescimento & desenvolvimento , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose , Proteínas Reguladoras de Apoptose , Biologia Computacional , Exorribonucleases/genética , Complexo Multienzimático de Ribonucleases do Exossomo/genética , Complexo Multienzimático de Ribonucleases do Exossomo/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Prosencéfalo/patologia , RNA/metabolismo , Estabilidade de RNA , Transdução de Sinais/genética , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor
2.
PLoS Genet ; 12(9): e1006274, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27611684

RESUMO

Neurogenesis is a key developmental event through which neurons are generated from neural stem/progenitor cells. Chromatin remodeling BAF (mSWI/SNF) complexes have been reported to play essential roles in the neurogenesis of the central nervous system. However, whether BAF complexes are required for neuron generation in the olfactory system is unknown. Here, we identified onscBAF and ornBAF complexes, which are specifically present in olfactory neural stem cells (oNSCs) and olfactory receptor neurons (ORNs), respectively. We demonstrated that BAF155 subunit is highly expressed in both oNSCs and ORNs, whereas high expression of BAF170 subunit is observed only in ORNs. We report that conditional deletion of BAF155, a core subunit in both onscBAF and ornBAF complexes, causes impaired proliferation of oNSCs as well as defective maturation and axonogenesis of ORNs in the developing olfactory epithelium (OE), while the high expression of BAF170 is important for maturation of ORNs. Interestingly, in the absence of BAF complexes in BAF155/BAF170 double-conditional knockout mice (dcKO), OE is not specified. Mechanistically, BAF complex is required for normal activation of Pax6-dependent transcriptional activity in stem cells/progenitors of the OE. Our findings unveil a novel mechanism mediated by the mSWI/SNF complex in OE neurogenesis and development.


Assuntos
Proteínas Cromossômicas não Histona/genética , Neurogênese , Mucosa Olfatória/metabolismo , Fatores de Transcrição/genética , Animais , Células Cultivadas , Proteínas Cromossômicas não Histona/metabolismo , Proteínas de Ligação a DNA , Deleção de Genes , Camundongos , Camundongos Endogâmicos C57BL , Mucosa Olfatória/citologia , Mucosa Olfatória/embriologia , Neurônios Receptores Olfatórios/citologia , Neurônios Receptores Olfatórios/metabolismo , Fatores de Transcrição/metabolismo
3.
Proc Natl Acad Sci U S A ; 108(6): 2575-80, 2011 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-21262811

RESUMO

Fusion between membranes is mediated by specific SNARE complexes. Here we report that fibroblasts survive the absence of the trans-Golgi network/early endosomal SNARE vti1a and the late endosomal SNARE vti1b with intact organelle morphology and minor trafficking defects. Because vti1a and vti1b are the only members of their SNARE subclass and the yeast homolog Vti1p is essential for cell survival, these data suggest that more distantly related SNAREs acquired the ability to function in endosomal traffic during evolution. However, absence of vti1a and vti1b resulted in perinatal lethality. Major axon tracts were missing, reduced in size, or misrouted in Vti1a(-/-) Vti1b(-/-) embryos. Progressive neurodegeneration was observed in most Vti1a(-/-) Vti1b(-/-) peripheral ganglia. Neurons were reduced by more than 95% in Vti1a(-/-) Vti1b(-/-) dorsal root and geniculate ganglia at embryonic day 18.5. These data suggest that special demands for endosomal membrane traffic could not be met in Vti1a(-/-) Vti1b(-/-) neurons. Vti1a(-/-) and Vti1b(-/-) single deficient mice were viable without these neuronal defects, indicating that they can substitute for each other in these processes.


Assuntos
Endossomos/metabolismo , Neurogênese/fisiologia , Neurônios/metabolismo , Proteínas Qb-SNARE/metabolismo , Animais , Transporte Biológico/fisiologia , Linhagem Celular Transformada , Endossomos/genética , Camundongos , Camundongos Knockout , Neurônios/citologia , Proteínas Qb-SNARE/genética
4.
Front Cell Dev Biol ; 10: 1011109, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36263009

RESUMO

Early forebrain patterning entails the correct regional designation of the neuroepithelium, and appropriate specification, generation, and distribution of neural cells during brain development. Specific signaling and transcription factors are known to tightly regulate patterning of the dorsal telencephalon to afford proper structural/functional cortical arealization and morphogenesis. Nevertheless, whether and how changes of the chromatin structure link to the transcriptional program(s) that control cortical patterning remains elusive. Here, we report that the BAF chromatin remodeling complex regulates the spatiotemporal patterning of the mouse dorsal telencephalon. To determine whether and how the BAF complex regulates cortical patterning, we conditionally deleted the BAF complex scaffolding subunits BAF155 and BAF170 in the mouse dorsal telencephalic neuroepithelium. Morphological and cellular changes in the BAF mutant forebrain were examined using immunohistochemistry and in situ hybridization. RNA sequencing, Co-immunoprecipitation, and mass spectrometry were used to investigate the molecular basis of BAF complex involvement in forebrain patterning. We found that conditional ablation of BAF complex in the dorsal telencephalon neuroepithelium caused expansion of the cortical hem and medial cortex beyond their developmental boundaries. Consequently, the hippocampal primordium is not specified, the mediolateral cortical patterning is compromised, and the cortical identity is disturbed in the absence of BAF complex. The BAF complex was found to interact with the cortical hem suppressor LHX2. The BAF complex suppresses cortical hem fate to permit proper forebrain patterning. We provide evidence that BAF complex modulates mediolateral cortical patterning possibly by interacting with the transcription factor LHX2 to drive the LHX2-dependent transcriptional program essential for dorsal telencephalon patterning. Our data suggest a putative mechanistic synergy between BAF chromatin remodeling complex and LHX2 in regulating forebrain patterning and ontogeny.

5.
Front Mol Neurosci ; 14: 687581, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220450

RESUMO

Radial neuronal migration is a key neurodevelopmental event indispensable for proper cortical laminar organization. Cortical neurons mainly use glial fiber guides, cell adhesion dynamics, and cytoskeletal remodeling, among other discrete processes, to radially trek from their birthplace to final layer positions. Dysregulated radial migration can engender cortical mis-lamination, leading to neurodevelopmental disorders. Epigenetic factors, including chromatin remodelers have emerged as formidable regulators of corticogenesis. Notably, the chromatin remodeler BAF complex has been shown to regulate several aspects of cortical histogenesis. Nonetheless, our understanding of how BAF complex regulates neuronal migration is limited. Here, we report that BAF complex is required for neuron migration during cortical development. Ablation of BAF complex in the developing mouse cortex caused alteration in the cortical gene expression program, leading to loss of radial migration-related factors critical for proper cortical layer formation. Of note, BAF complex inactivation in cortex caused defective neuronal polarization resulting in diminished multipolar-to-bipolar transition and eventual disruption of radial migration of cortical neurons. The abnormal radial migration and cortical mis-lamination can be partly rescued by downregulating WNT signaling hyperactivity in the BAF complex mutant cortex. By implication, the BAF complex modulates WNT signaling to establish the gene expression program required for glial fiber-dependent neuronal migration, and cortical lamination. Overall, BAF complex has been identified to be crucial for cortical morphogenesis through instructing multiple aspects of radial neuronal migration in a WNT signaling-dependent manner.

6.
Stem Cell Reports ; 16(4): 968-984, 2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33798452

RESUMO

Intermediate progenitor cells (IPCs) are neocortical neuronal precursors. Although IPCs play crucial roles in corticogenesis, their molecular features remain largely unknown. In this study, we aimed to characterize the molecular profile of IPCs. We isolated TBR2-positive (+) IPCs and TBR2-negative (-) cell populations in the developing mouse cortex. Comparative genome-wide gene expression analysis of TBR2+ IPCs versus TBR2- cells revealed differences in key factors involved in chromatid segregation, cell-cycle regulation, transcriptional regulation, and cell signaling. Notably, mutation of many IPC genes in human has led to intellectual disability and caused a wide range of cortical malformations, including microcephaly and agenesis of corpus callosum. Loss-of-function experiments in cortex-specific mutants of Esco2, one of the novel IPC genes, demonstrate its critical role in IPC maintenance, and substantiate the identification of a central genetic determinant of IPC biogenesis. Our data provide novel molecular characteristics of IPCs in the developing mouse cortex.


Assuntos
Acetiltransferases/metabolismo , Córtex Cerebral/citologia , Córtex Cerebral/embriologia , Perfilação da Expressão Gênica , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Acetiltransferases/genética , Animais , Apoptose/genética , Cromátides/metabolismo , Segregação de Cromossomos/genética , Regulação da Expressão Gênica , Humanos , Camundongos , Mitose/genética , Mutação/genética , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Transdução de Sinais
7.
Neuroscience ; 463: 303-316, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-33774122

RESUMO

Cortical morphogenesis entails several neurobiological events, including proliferation and differentiation of progenitors, migration of neuroblasts, and neuronal maturation leading to functional neural circuitry. These neurodevelopmental processes are delicately regulated by many factors. Endosomal SNAREs have emerged as formidable modulators of neuronal growth, aside their well-known function in membrane/vesicular trafficking. However, our understanding of their influence on cortex formation is limited. Here, we report that the SNAREs Vti1a and Vti1b (Vti1a/1b) are critical for proper cortical development. Following null mutation of Vti1a/1b in mouse, the late-embryonic mutant cortex appeared dysgenic, and the cortical progenitors therein were depleted beyond normal. Notably, cortical layer 5 (L5) is distinctively disorganized in the absence of Vti1a/1b. The latter defect, coupled with an overt apoptosis of Ctip2-expressing L5 neurons, likely contributed to the substantial loss of corticospinal and callosal projections in the Vti1a/1b-deficient mouse brain. These findings suggest that Vti1a/1b serve key neurodevelopmental functions during cortical histogenesis, which when mechanistically elucidated, can lend clarity to how endosomal SNAREs regulate brain development, or how their dysfunction may have implications for neurological disorders.


Assuntos
Células-Tronco Neurais , Neurônios , Animais , Diferenciação Celular , Córtex Cerebral/metabolismo , Camundongos , Células-Tronco Neurais/metabolismo , Neurogênese , Neurônios/metabolismo , Proteínas Qb-SNARE/metabolismo , Proteínas SNARE/metabolismo
8.
Sci Adv ; 7(38): eabc6792, 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34524839

RESUMO

Increase in the size of human neocortex­acquired in evolution­accounts for the unique cognitive capacity of humans. This expansion reflects the evolutionarily enhanced proliferative ability of basal progenitors (BPs), including the basal radial glia and basal intermediate progenitors (bIPs) in mammalian cortex, which may have been acquired through epigenetic alterations in BPs. However, how the epigenome in BPs differs across species is not known. Here, we report that histone H3 acetylation is a key epigenetic regulation in bIP amplification and cortical expansion. Through epigenetic profiling of sorted bIPs, we show that histone H3 lysine 9 acetylation (H3K9ac) is low in murine bIPs and high in human bIPs. Elevated H3K9ac preferentially increases bIP proliferation, increasing the size and folding of the normally smooth mouse neocortex. H3K9ac drives bIP amplification by increasing expression of the evolutionarily regulated gene, Trnp1, in developing cortex. Our findings demonstrate a previously unknown mechanism that controls cortical architecture.

9.
Int J Dev Neurosci ; 27(1): 97-102, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18824086

RESUMO

Neurotrophic factors are well-recognized extracellular signaling molecules that regulate neuron development including neurite growth, survival and maturation of neuronal phenotypes in the central and peripheral nervous system. Previous studies have suggested that TGF-beta plays a key role in the regulation of neuron survival and death and potentiates the neurotrophic activity of several neurotrophic factors, most strikingly of GDNF. To test the physiological relevance of this finding, TGF-beta2/GDNF double mutant (d-ko) mice were generated. Double mutant mice die at birth like single mutants due to kidney agenesis (GDNF-/-) and congential cyanosis (TGF-beta2-/-), respectively. To test for the in vivo relevance of TGF-beta2/GDNF cooperativity to regulate neuron survival, mesencephalic dopaminergic neurons, lumbar motoneurons, as well as neurons of the lumbar dorsal root ganglion and the superior cervical ganglion were investigated. No loss of mesencephalic dopaminergic neurons was observed in double mutant mice at E18.5. A partial reduction in neuron numbers was observed in lumbar motoneurons, sensory and sympathetic neurons in GDNF single mutants, which was further reduced in TGF-beta2/GDNF double mutant mice at E18.5. However, TGF-beta2 single mutant mice showed no loss of neurons. These data point towards a cooperative role of TGF-beta2 and GDNF with regard to promotion of survival within the peripheral motor and sensory systems investigated.


Assuntos
Sistema Nervoso Autônomo/anormalidades , Sistema Nervoso Central/anormalidades , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Neurogênese/genética , Sistema Nervoso Periférico/anormalidades , Fator de Crescimento Transformador beta/genética , Animais , Sistema Nervoso Autônomo/citologia , Sistema Nervoso Autônomo/metabolismo , Contagem de Células , Morte Celular/genética , Sobrevivência Celular/genética , Sistema Nervoso Central/citologia , Sistema Nervoso Central/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Camundongos , Camundongos Knockout , Neurônios Motores/citologia , Neurônios Motores/metabolismo , Sistema Nervoso Periférico/citologia , Sistema Nervoso Periférico/metabolismo , Células Receptoras Sensoriais/citologia , Células Receptoras Sensoriais/metabolismo
10.
Mol Neurobiol ; 56(11): 7305-7320, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31020615

RESUMO

Chromatin remodeling factor BAF155 is an important regulator of many biological processes. As a core and scaffold subunit of the BAF (SWI/SNF-like) complex, BAF155 is capable of regulating the stability and function of the BAF complex. The spatiotemporal expression of BAF155 during embryogenesis is essential for various aspects of organogenesis, particularly in the brain development. However, our understanding of the mechanisms that regulate the expression and function of BAF155 is limited. Here, we report that RBM15, a subunit of the m6A methyltransferase complex, interacts with BAF155 mRNA and mediates BAF155 mRNA degradation through the mRNA methylation machinery. Ablation of endogenous RBM15 expression in cultured neuronal cells and in the developing cortex augmented the expression of BAF155. Conversely, RBM15 overexpression decreased BAF155 mRNA and protein levels, and perturbed BAF155 functions in vivo, including repression of BAF155-dependent transcriptional activity and delamination of apical radial glial progenitors as a hallmark of basal radial glial progenitor genesis. Furthermore, we demonstrated that the regulation of BAF155 by RBM15 depends on the activity of the mRNA methylation complex core catalytic subunit METTL3. Altogether, our findings reveal a new regulatory avenue that elucidates how BAF complex subunit stoichiometry and functional modulation are achieved in mammalian cells.


Assuntos
Córtex Cerebral/embriologia , Córtex Cerebral/metabolismo , Montagem e Desmontagem da Cromatina , Proteínas de Ligação a RNA/metabolismo , RNA/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Junções Aderentes/metabolismo , Animais , Linhagem Celular , Humanos , Metilação , Metiltransferases/metabolismo , Camundongos , Modelos Biológicos , Neuroglia/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Fatores de Transcrição
11.
Front Neurosci ; 12: 226, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29686607

RESUMO

The generation of individual neurons (neurogenesis) during cortical development occurs in discrete steps that are subtly regulated and orchestrated to ensure normal histogenesis and function of the cortex. Notably, various gene expression programs are known to critically drive many facets of neurogenesis with a high level of specificity during brain development. Typically, precise regulation of gene expression patterns ensures that key events like proliferation and differentiation of neural progenitors, specification of neuronal subtypes, as well as migration and maturation of neurons in the developing cortex occur properly. ATP-dependent chromatin remodeling complexes regulate gene expression through utilization of energy from ATP hydrolysis to reorganize chromatin structure. These chromatin remodeling complexes are characteristically multimeric, with some capable of adopting functionally distinct conformations via subunit reconstitution to perform specific roles in major aspects of cortical neurogenesis. In this review, we highlight the functions of such chromatin remodelers during cortical development. We also bring together various proposed mechanisms by which ATP-dependent chromatin remodelers function individually or in concert, to specifically modulate vital steps in cortical neurogenesis.

12.
Mol Neurobiol ; 55(11): 8306-8327, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29532253

RESUMO

The postnatal mammalian olfactory epithelium (OE) represents a major aspect of the peripheral olfactory system. It is a pseudostratified tissue that originates from the olfactory placode and is composed of diverse cells, some of which are specialized receptor neurons capable of transducing odorant stimuli to afford the perception of smell (olfaction). The OE is known to offer a tractable miniature model for studying the systematic generation of neurons and glia that typify neural tissue development. During OE development, stem/progenitor cells that will become olfactory sensory neurons and/or non-neuronal cell types display fine spatiotemporal expression of neuronal and non-neuronal genes that ensures their proper proliferation, differentiation, survival, and regeneration. Many factors, including transcription and epigenetic factors, have been identified as key regulators of the expression of such requisite genes to permit normal OE morphogenesis. Typically, specific interactive regulatory networks established between transcription and epigenetic factors/cofactors orchestrate histogenesis in the embryonic and adult OE. Hence, investigation of these regulatory networks critical for OE development promises to disclose strategies that may be employed in manipulating the stepwise transition of olfactory precursor cells to become fully differentiated and functional neuronal and non-neuronal cell types. Such strategies potentially offer formidable means of replacing injured or degenerated neural cells as therapeutics for nervous system perturbations. This review recapitulates the developmental cellular diversity of the olfactory neuroepithelium and discusses findings on how the precise and cooperative molecular control by transcriptional and epigenetic machinery is indispensable for OE ontogeny.


Assuntos
Mamíferos/genética , Mucosa Olfatória/embriologia , Mucosa Olfatória/metabolismo , Animais , Montagem e Desmontagem da Cromatina , Epigênese Genética , Mucosa Olfatória/citologia , Transcrição Gênica
13.
Stem Cell Reports ; 10(6): 1734-1750, 2018 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-29779894

RESUMO

During early cortical development, neural stem cells (NSCs) divide symmetrically to expand the progenitor pool, whereas, in later stages, NSCs divide asymmetrically to self-renew and produce other cell types. The timely switch from such proliferative to differentiative division critically determines progenitor and neuron numbers. However, the mechanisms that limit proliferative division in late cortical development are not fully understood. Here, we show that the BAF (mSWI/SNF) complexes restrict proliferative competence and promote neuronal differentiation in late corticogenesis. Inactivation of BAF complexes leads to H3K27me3-linked silencing of neuronal differentiation-related genes, with concurrent H3K4me2-mediated activation of proliferation-associated genes via de-repression of Wnt signaling. Notably, the deletion of BAF complexes increased proliferation of neuroepithelial cell-like NSCs, impaired neuronal differentiation, and exerted a Wnt-dependent effect on neocortical and hippocampal development. Thus, these results demonstrate that BAF complexes act as both activators and repressors to control global epigenetic and gene expression programs in late corticogenesis.


Assuntos
Proteínas Cromossômicas não Histona/metabolismo , Desenvolvimento Embrionário/genética , Epigênese Genética , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Ribonucleoproteínas/metabolismo , Via de Sinalização Wnt , Animais , Diferenciação Celular , Proliferação de Células , Montagem e Desmontagem da Cromatina , Proteínas Cromossômicas não Histona/genética , Imunofluorescência , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Inativação de Genes , Hipocampo/embriologia , Hipocampo/metabolismo , Camundongos , Neurogênese , Neurônios/citologia , Neurônios/metabolismo , Ligação Proteica , Ribonucleoproteínas/genética
14.
iScience ; 4: 109-126, 2018 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-30240734

RESUMO

The abundance of basal progenitors (BPs), basal radial glia progenitors (bRGs) and basal intermediate progenitors (bIPs), in primate brain has been correlated to the high degree of cortical folding. Here we examined the role of BAF155, a subunit of the chromatin remodeling BAF complex, in generation of cortical progenitor heterogeneity. The conditional deletion of BAF155 led to diminished bIP pool and increased number of bRGs, due to delamination of apical RGs. We found that BAF155 is required for normal activity of neurogenic transcription factor PAX6, thus controlling the expression of genes that are involved in bIP specification, cell-cell interaction, and establishment of adherens junction. In a PAX6-dependent manner, BAF155 regulates the expression of the CDC42 effector protein CEP4, thereby controlling progenitor delamination. Furthermore, BAF155-dependent chromatin remodeling seems to exert a specific role in the genesis of BPs through the regulation of human RG-specific genes (such as Foxn4) that possibly acquired evolutionary significance.

15.
Front Mol Neurosci ; 10: 243, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28824374

RESUMO

The ATP-dependent BRG1/BRM associated factor (BAF) chromatin remodeling complexes are crucial in regulating gene expression by controlling chromatin dynamics. Over the last decade, it has become increasingly clear that during neural development in mammals, distinct ontogenetic stage-specific BAF complexes derived from combinatorial assembly of their subunits are formed in neural progenitors and post-mitotic neural cells. Proper functioning of the BAF complexes plays critical roles in neural development, including the establishment and maintenance of neural fates and functionality. Indeed, recent human exome sequencing and genome-wide association studies have revealed that mutations in BAF complex subunits are linked to neurodevelopmental disorders such as Coffin-Siris syndrome, Nicolaides-Baraitser syndrome, Kleefstra's syndrome spectrum, Hirschsprung's disease, autism spectrum disorder, and schizophrenia. In this review, we focus on the latest insights into the functions of BAF complexes during neural development and the plausible mechanistic basis of how mutations in known BAF subunits are associated with certain neurodevelopmental disorders.

16.
Cell Cycle ; 15(10): 1317-24, 2016 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-26986003

RESUMO

The multi-subunit chromatin-remodeling SWI/SNF (known as BAF for Brg/Brm-associated factor) complexes play essential roles in development. Studies have shown that the loss of individual BAF subunits often affects local chromatin structure and specific transcriptional programs. However, we do not fully understand how BAF complexes function in development because no animal mutant had been engineered to lack entire multi-subunit BAF complexes. Importantly, we recently reported that double conditional knock-out (dcKO) of the BAF155 and BAF170 core subunits in mice abolished the presence of the other BAF subunits in the developing cortex. The generated dcKO mutant provides a novel and powerful tool for investigating how entire BAF complexes affect cortical development. Using this model, we found that BAF complexes globally control the key heterochromatin marks, H3K27me2 and -3, by directly modulating the enzymatic activity of the H3K27 demethylases, Utx and Jmjd3. Here, we present further insights into how the scaffolding ability of the BAF155 and BAF170 core subunits maintains the stability of BAF complexes in the forebrain and throughout the embryo during development. Furthermore, we show that the loss of BAF complexes in the above-described model up-regulates H3K27me3 and impairs forebrain development and embryogenesis. These findings improve our understanding of epigenetic mechanisms and their modulation by the chromatin-remodeling SWI/SNF complexes that control embryonic development.


Assuntos
Cromatina/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Epigênese Genética , Animais , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Montagem e Desmontagem da Cromatina , Proteínas Cromossômicas não Histona/deficiência , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA , Desenvolvimento Embrionário , Histona Desmetilases/metabolismo , Histonas/metabolismo , Imuno-Histoquímica , Histona Desmetilases com o Domínio Jumonji/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética
17.
Cell Rep ; 13(9): 1842-54, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26655900

RESUMO

BAF (Brg/Brm-associated factors) complexes play important roles in development and are linked to chromatin plasticity at selected genomic loci. Nevertheless, a full understanding of their role in development and chromatin remodeling has been hindered by the absence of mutants completely lacking BAF complexes. Here, we report that the loss of BAF155/BAF170 in double-conditional knockout (dcKO) mice eliminates all known BAF subunits, resulting in an overall reduction in active chromatin marks (H3K9Ac), a global increase in repressive marks (H3K27me2/3), and downregulation of gene expression. We demonstrate that BAF complexes interact with H3K27 demethylases (JMJD3 and UTX) and potentiate their activity. Importantly, BAF complexes are indispensable for forebrain development, including proliferation, differentiation, and cell survival of neural progenitor cells. Our findings reveal a molecular mechanism mediated by BAF complexes that controls the global transcriptional program and chromatin state in development.


Assuntos
Cromatina/metabolismo , Proteínas Cromossômicas não Histona/genética , Fatores de Transcrição/genética , Animais , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Córtex Cerebelar/metabolismo , Proteínas Cromossômicas não Histona/deficiência , Proteínas Cromossômicas não Histona/metabolismo , DNA Helicases/metabolismo , Proteínas de Ligação a DNA , Regulação para Baixo , Embrião de Mamíferos/metabolismo , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Histonas/genética , Histonas/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Transcrição/deficiência , Fatores de Transcrição/metabolismo
18.
Mol Cell Neurosci ; 21(4): 584-601, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12504592

RESUMO

Aberrant reorganization of hippocampal mossy fibers occurs in human temporal lobe epilepsy and rodent epilepsy models. We generated a mouse model showing massive late-onset aberrant mossy fiber sprouting in the adult hippocampus. The mutation in this mouse model derives from an intronic insertion of transgene DNA in the mouse PLC-beta1 gene (PLC-beta 1(-/-)(TC) mutation) leading to a splice mutation of the PLC-beta 1 gene and a complete loss of downstream PLC-beta 1 expression. PLC-beta 1(-/-)(TC) mutants develop a loss of NMDA-receptors in the stratum oriens of region CA1, apoptotic neuronal death, and reduced hippocampal PKC activity. The phenotype of these mice further consists of a late-onset epileptiform hyperexcitability, behavioral modifications in a radial maze and in an open field, female nurturing defect, and male infertility. In the present study, we provide evidence that the arising of the behavioral phenotype in PLC-beta 1(-/-)(TC) mice correlates in time with the development of the aberrant mossy fiber projections and that the disruption of the PLC-beta 1-mediated signal transduction pathway may lead to a functional cholinergic denervation, which could cause hippocampal remodeling and, in consequence, epileptiform hyperexcitability.


Assuntos
Envelhecimento/genética , Epilepsia do Lobo Temporal/genética , Isoenzimas/deficiência , Fibras Musgosas Hipocampais/enzimologia , Degeneração Neural/genética , Transdução de Sinais/genética , Fosfolipases Tipo C/deficiência , Envelhecimento/metabolismo , Processamento Alternativo/genética , Animais , Carbacol/farmacologia , Mapeamento Cromossômico , Modelos Animais de Doenças , Epilepsia do Lobo Temporal/enzimologia , Epilepsia do Lobo Temporal/fisiopatologia , Feminino , Cones de Crescimento/enzimologia , Isoenzimas/genética , Masculino , Camundongos , Camundongos Knockout , Camundongos Mutantes Neurológicos , Fibras Musgosas Hipocampais/patologia , Mutação/genética , Degeneração Neural/enzimologia , Degeneração Neural/fisiopatologia , Plasticidade Neuronal/genética , Fosfolipase C beta , Proteína Quinase C/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Proteínas Recombinantes de Fusão/genética , Transgenes/genética , Fosfolipases Tipo C/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA