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1.
Stem Cells ; 36(11): 1736-1751, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29999568

RESUMO

Adult neurogenesis in the brain continuously seeds new neurons throughout life, but how homeostasis of adult neural stem cells (NSCs) is maintained is incompletely understood. Here, we demonstrate that the DNA methylation adapter ubiquitin-like, containing PHD and RING finger domains-1 (UHRF1) is expressed in, and regulates proliferation of, the active but not quiescent pool of adult neural progenitor cells. Mice with a neural stem cell-specific deficiency in UHRF1 exhibit a massive depletion of neurogenesis resulting in a collapse of formation of new neurons. In the absence of UHRF1, NSCs unexpectedly remain in the cell cycle but with a 17-fold increased cell cycle length due to a failure of replication phase entry caused by promoter demethylation and derepression of Cdkn1a, which encodes the cyclin-dependent kinase inhibitor p21. UHRF1 does not affect the proportion progenitor cells active within the cell cycle but among these cells, UHRF1 is critical for licensing replication re-entry. Therefore, this study shows that a UHRF1-Cdkn1a axis is essential for the control of stem cell self-renewal and neurogenesis in the adult brain. Stem Cells 2018;36:1736-1751.


Assuntos
Células-Tronco Adultas/metabolismo , Células-Tronco Neurais/metabolismo , Proteínas Nucleares/genética , Animais , Proteínas Estimuladoras de Ligação a CCAAT , Humanos , Camundongos , Proteínas Nucleares/metabolismo , Ubiquitina-Proteína Ligases
2.
Development ; 139(2): 397-410, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22186729

RESUMO

The cellular origin and molecular mechanisms regulating pigmentation of head and neck are largely unknown. Melanocyte specification is controlled by the transcriptional activity of Mitf, but no general logic has emerged to explain how Mitf and progenitor transcriptional activities consolidate melanocyte and progenitor cell fates. We show that cranial melanocytes arise from at least two different cellular sources: initially from nerve-associated Schwann cell precursors (SCPs) and later from a cellular source that is independent of nerves. Unlike the midbrain-hindbrain cluster from which melanoblasts arise independently of nerves, a large center of melanocytes in and around cranial nerves IX-X is derived from SCPs, as shown by genetic cell-lineage tracing and analysis of ErbB3-null mutant mice. Conditional gain- and loss-of-function experiments show genetically that cell fates in the neural crest involve both the SRY transcription factor Sox2 and Mitf, which consolidate an SCP progenitor or melanocyte fate by cross-regulatory interactions. A gradual downregulation of Sox2 in progenitors during development permits the differentiation of both neural crest- and SCP-derived progenitors into melanocytes, and an initial small pool of nerve-associated melanoblasts expands in number and disperses under the control of endothelin receptor B (Ednrb) and Wnt5a signaling.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Melanócitos/citologia , Fator de Transcrição Associado à Microftalmia/metabolismo , Crista Neural/embriologia , Pigmentação/fisiologia , Fatores de Transcrição SOXB1/metabolismo , Animais , Imunoprecipitação da Cromatina , Embrião de Mamíferos/embriologia , Imageamento Tridimensional , Imuno-Histoquímica , Hibridização In Situ , Melanócitos/metabolismo , Camundongos , Crista Neural/metabolismo , Plasmídeos/genética , RNA Interferente Pequeno/genética , Receptores de Endotelina/metabolismo , Células de Schwann/citologia , Transdução de Sinais/fisiologia , Proteínas Wnt/metabolismo , Proteína Wnt-5a
3.
Eur J Neurosci ; 27(11): 2838-46, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18588529

RESUMO

Synaptogenesis is essential for the development of neuronal networks in the brain. In the olfactory bulb (OB) glomeruli, numerous synapses must form between sensory olfactory neurons and the dendrites of mitral/tufted and periglomerular cells. Glomeruli develop from E13 to E16 in the mouse, coincident with an increment of the neuropil in the border between the external plexiform (EPL) and olfactory nerve layers (ONL), coupled to an extensive labelling of phalloidin and GAP-43 from the ONL to EPL. We have tracked synaptogenesis in the OB during this period by electron microscopy (EM) and immunolabelling of the transmembrane synaptic vesicle glycoprotein SV-2. No SV-2 labelling or synapses were detected at E13, although electrodense junctions lacking synaptic vesicles could be observed by EM. At E14, sparse SV-2 labelling appears in the most ventral and medial part of the incipient OB, which displays a ventro-dorsal gradient by E15 but covers the entire OB by E16. These data establish a spatio-temporal pattern of synaptogenesis, which perfectly matches with the glomeruli formation in developing OB.


Assuntos
Diferenciação Celular/fisiologia , Neurópilo/ultraestrutura , Bulbo Olfatório/embriologia , Bulbo Olfatório/ultraestrutura , Sinapses/ultraestrutura , Animais , Biomarcadores/análise , Biomarcadores/metabolismo , Dendritos/metabolismo , Dendritos/ultraestrutura , Proteína GAP-43/metabolismo , Glicoproteínas de Membrana/metabolismo , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Neurópilo/metabolismo , Bulbo Olfatório/metabolismo , Mucosa Olfatória/embriologia , Mucosa Olfatória/metabolismo , Mucosa Olfatória/ultraestrutura , Neurônios Receptores Olfatórios/embriologia , Neurônios Receptores Olfatórios/metabolismo , Neurônios Receptores Olfatórios/ultraestrutura , Faloidina/metabolismo , Sinapses/metabolismo , Membranas Sinápticas/metabolismo , Membranas Sinápticas/ultraestrutura , Transmissão Sináptica/fisiologia , Vesículas Sinápticas/metabolismo , Vesículas Sinápticas/ultraestrutura , Fatores de Tempo
4.
J Comp Neurol ; 496(4): 529-43, 2006 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-16572431

RESUMO

Along with tufted cells, mitral cells are the principal projection neurons in the olfactory bulb (OB). During the development of the OB, mitral cells migrate from the ventricular zone to the intermediate zone, where they begin to send axons along the lateral olfactory tract (LOT) to the cortical olfactory zones. Subsequently, they lose their tangential orientation, enabling them to make contact with the axons of the olfactory sensory neurons (OSN) that innervate the whole OB. Here, we investigated the distinct morphological features displayed by developing mitral cells and analyzed the relationship between the changes undertaken by these neurons and the arrival of the OSN axons. Immunostaining for specific markers of developing axons and dendrites, coupled with the use of fluorescent tracers, revealed the morphological changes, the continuous reorientation, and the final refinement that these cells undergo. We found that some of these changes are dependent on the arrival of the OSN axons. Indeed, we identified three main chronological events: 1) newly generated neurons become established in the intermediate zone and project to the LOT; 2) the cells reorient and spread their dendrites at the same time as OSN axons penetrate the OB (this is a sensitive period between embryonic day (E)15-16, in which the arrival of afferents establishes a spatial and temporal gradient that facilitates protoglomerulus and glomerulus formation); and 3) final refinement of the radially orientated cells to adopt a mature morphology. These results suggest that both afferent inputs and intrinsic factors participate to produce the well-defined sensory system.


Assuntos
Envelhecimento/fisiologia , Diferenciação Celular/fisiologia , Neurônios/citologia , Bulbo Olfatório/citologia , Condutos Olfatórios/citologia , Animais , Proliferação de Células , Camundongos , Bulbo Olfatório/crescimento & desenvolvimento , Condutos Olfatórios/crescimento & desenvolvimento , Neurônios Receptores Olfatórios/citologia , Neurônios Receptores Olfatórios/crescimento & desenvolvimento , Fatores de Tempo
5.
PLoS One ; 6(10): e26673, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22046330

RESUMO

Dab1 mediates reelin signalling and plays critical roles in early brain development such as the stereotypical positioning of neurons in the brain. The olfactory bulb undergoes a prominent layering reorganization, but shows not apparent differences between wild type and reeler in the layer organization. Therefore, an accurate regional and cellular simultaneous analysis of these molecules becomes essential to clarify the role played by Dab1 upon Reelin effect. The present study reveals a strong and consistent Dab1 mRNA and protein expressions, throughout the olfactory bulb layers in both wild type and reeler mice. In addition, noteworthy is the pattern of Dab1 location within cell nuclei in both strains. Furthermore, a temporal increment of Dab1 expression levels is detected from P0 to P15 in both strains, being the protein quantity higher in reeler than in wild type mice. Altogether, our results revealed that Reln acts directly from projection neurons via the production of different Reln fragments. Changes in the pattern of Dab1 expression could reflect an alternative Reln function in postnatal and adult stages, besides a possible regulation of Dab1 by other molecules distinct to Reln.


Assuntos
Moléculas de Adesão Celular Neuronais/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Proteínas do Tecido Nervoso/metabolismo , Bulbo Olfatório/metabolismo , Serina Endopeptidases/metabolismo , Animais , Animais Recém-Nascidos , Expressão Gênica , Camundongos , Camundongos Mutantes Neurológicos , Proteínas do Tecido Nervoso/análise , Proteínas do Tecido Nervoso/genética , Neurônios , RNA Mensageiro/análise , Proteína Reelina , Fatores de Tempo
6.
Dev Dyn ; 232(2): 325-35, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15614760

RESUMO

We have established previously that, although the olfactory epithelium is absent in the homozygous Pax-6 mutant mouse, an olfactory bulb-like structure (OBLS) does develop. Moreover, this OBLS contains cells that correspond to mitral cells, the primary projection neurons in the olfactory bulb. The current study aimed to address whether the dendrites of mitral cells in the olfactory bulb or in the OBLS mitral-like cells, exhibit a change in orientation in the presence of the olfactory epithelium. The underlying hypothesis is that the olfactory epithelium imparts a trophic signal on mitral and mitral-like cell that influences the growth of their primary dendrites, orientating them toward the surface of the olfactory bulb. Hence, we cultured hemibrains from wild-type and Pax 6 mutant mice from two different embryonic stages (embryonic days 14 and 15) either alone or in coculture with normal olfactory epithelial explants or control tissue (cerebellum). Our results indicate that the final dendritic orientation of mitral and mitral-like cells is directly influenced both by age and indeed by the presence of the olfactory epithelium.


Assuntos
Dendritos/metabolismo , Epitélio/embriologia , Epitélio/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Mucosa Olfatória/embriologia , Mucosa Olfatória/metabolismo , Neurônios Receptores Olfatórios/embriologia , Animais , Encéfalo/metabolismo , Carbocianinas/química , Células Cultivadas , Técnicas de Cocultura , Colágeno/química , Corantes/farmacologia , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , Proteínas do Olho/fisiologia , Heterozigoto , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Proteínas de Homeodomínio/fisiologia , Homozigoto , Camundongos , Microscopia de Fluorescência , Mutação , Neurônios/metabolismo , Fator de Transcrição PAX6 , Fatores de Transcrição Box Pareados , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Proteínas Repressoras/fisiologia , Telencéfalo/metabolismo , Fatores de Tempo
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