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1.
Development ; 147(10)2020 05 26.
Artículo en Inglés | MEDLINE | ID: mdl-32253238

RESUMEN

The transcription factor Zeb2 controls fate specification and subsequent differentiation and maturation of multiple cell types in various embryonic tissues. It binds many protein partners, including activated Smad proteins and the NuRD co-repressor complex. How Zeb2 subdomains support cell differentiation in various contexts has remained elusive. Here, we studied the role of Zeb2 and its domains in neurogenesis and neural differentiation in the young postnatal ventricular-subventricular zone (V-SVZ), in which neural stem cells generate olfactory bulb-destined interneurons. Conditional Zeb2 knockouts and separate acute loss- and gain-of-function approaches indicated that Zeb2 is essential for controlling apoptosis and neuronal differentiation of V-SVZ progenitors before and after birth, and we identified Sox6 as a potential downstream target gene of Zeb2. Zeb2 genetic inactivation impaired the differentiation potential of the V-SVZ niche in a cell-autonomous fashion. We also provide evidence that its normal function in the V-SVZ also involves non-autonomous mechanisms. Additionally, we demonstrate distinct roles for Zeb2 protein-binding domains, suggesting that Zeb2 partners co-determine neuronal output from the mouse V-SVZ in both quantitative and qualitative ways in early postnatal life.


Asunto(s)
Ventrículos Laterales/embriología , Ventrículos Laterales/crecimiento & desarrollo , Neurogénesis/genética , Bulbo Olfatorio/embriología , Bulbo Olfatorio/crecimiento & desarrollo , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/metabolismo , Animales , Apoptosis/genética , Movimiento Celular/genética , Proliferación Celular/genética , Técnicas de Inactivación de Genes , Interneuronas/metabolismo , Ventrículos Laterales/metabolismo , Ratones , Ratones Noqueados , Células-Madre Neurales/metabolismo , Bulbo Olfatorio/metabolismo , Factores de Transcripción SOXD/metabolismo , Transducción de Señal/inmunología , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/genética
2.
Hum Mol Genet ; 29(18): 3032-3043, 2020 11 04.
Artículo en Inglés | MEDLINE | ID: mdl-32879944

RESUMEN

The human UBE3A gene, which is essential for normal neurodevelopment, encodes three Ubiquitin E3 ligase A (UBE3A) protein isoforms. However, the subcellular localization and relative abundance of these human UBE3A isoforms are unknown. We found, as previously reported in mice, that UBE3A is predominantly nuclear in human neurons. However, this conserved subcellular distribution is achieved by strikingly distinct cis-acting mechanisms. A single amino-acid deletion in the N-terminus of human hUBE3A-Iso3, which is homologous to cytosolic mouse mUBE3A-Iso2, results in its translocation to the nucleus. This singe amino-acid deletion is shared with apes and Old World monkeys and was preceded by the appearance of the cytosolic hUBE3A-Iso2 isoform. This hUBE3A-Iso2 isoform arose after the lineage of New World monkeys and Old World monkeys separated from the Tarsiers (Tarsiidae). Due to the loss of a single nucleotide in a non-coding exon, this exon became in frame with the remainder of the UBE3A protein. RNA-seq analysis of human brain samples showed that the human UBE3A isoforms arise by alternative splicing. Consistent with the predominant nuclear enrichment of UBE3A in human neurons, the two nuclear-localized isoforms, hUBE3A-Iso1 and -Iso3, are the most abundantly expressed isoforms of UBE3A, while hUBE3A-Iso2 maintains a small pool of cytosolic UBE3A. Our findings provide new insight into UBE3A localization and evolution and may have important implications for gene therapy approaches in Angelman syndrome.


Asunto(s)
Síndrome de Angelman/genética , Neuronas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Empalme Alternativo/genética , Síndrome de Angelman/patología , Animales , Encéfalo/metabolismo , Encéfalo/patología , Impresión Genómica/genética , Humanos , Ratones , Neuronas/patología , Isoformas de Proteínas/genética
3.
Hum Genet ; 141(12): 1837-1848, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-35637341

RESUMEN

Angelman syndrome is a rare neurodevelopmental disorder caused by mutations affecting the chromosomal 15q11-13 region, either by contiguous gene deletions, imprinting defects, uniparental disomy, or mutations in the UBE3A gene itself. Phenotypic abnormalities are driven primarily, but not exclusively (especially in 15q11-13 deletion cases) by loss of expression of the maternally inherited UBE3A gene expression. The disorder was first described in 1965 by the English pediatrician Harry Angelman. Since that first description of three children with Angelman syndrome, there has been extensive research into the genetic, molecular and phenotypic aspects of the disorder. In the last decade, this has resulted in over 100 publications per year. Collectively, this research has led the field to a pivotal point in which restoring UBE3A function by genetic therapies is currently explored in several clinical trials. In this study, we employed a bibliometric approach to review and visualize the development of Angelman syndrome research over the last 50 years. We look into different parameters shaping the progress of the Angelman syndrome research field, including source of funding, publishing journals and international collaborations between research groups. Using a network approach, we map the focus of the research field and how that shifted over time. This overview helps understand the shift of research focus in the field and can provide a comprehensive handbook of Angelman syndrome research development.


Asunto(s)
Síndrome de Angelman , Niño , Humanos , Síndrome de Angelman/genética , Síndrome de Angelman/terapia , Ubiquitina-Proteína Ligasas/genética , Mutación , Bibliometría , Cromosomas Humanos Par 15
4.
Sci Rep ; 11(1): 3007, 2021 02 04.
Artículo en Inglés | MEDLINE | ID: mdl-33542309

RESUMEN

Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by brain-specific loss of UBE3A, an E3 ubiquitin protein ligase. A substantial number of possible ubiquitination targets of UBE3A have been identified, although evidence of being direct UBE3A substrates is often lacking. Here we identified the synaptic protein Rabphilin-3a (RPH3A), an effector of the RAB3A small GTPase involved in axonal vesicle priming and docking, as a ubiquitination target of UBE3A. We found that the UBE3A and RAB3A binding sites on RPH3A partially overlap, and that RAB3A binding to RPH3A interferes with UBE3A binding. We confirmed previous observations that RPH3A levels are critically dependent on RAB3A binding but, rather surprisingly, we found that the reduced RPH3A levels in the absence of RAB3A are not mediated by UBE3A. Indeed, while we found that RPH3A is ubiquitinated in a UBE3A-dependent manner in mouse brain, UBE3A mono-ubiquitinates RPH3A and does not facilitate RPH3A degradation. Moreover, we found that an AS-linked UBE3A missense mutation in the UBE3A region that interacts with RPH3A, abrogates the interaction with RPH3A. In conclusion, our results identify RPH3A as a novel target of UBE3A and suggest that UBE3A-dependent ubiquitination of RPH3A serves a non-degradative function.

5.
Cell Rep Med ; 2(8): 100360, 2021 08 17.
Artículo en Inglés | MEDLINE | ID: mdl-34467244

RESUMEN

Angelman syndrome (AS) is a neurodevelopmental disorder caused by the loss of maternal UBE3A, a ubiquitin protein ligase E3A. Here, we study neurons derived from patients with AS and neurotypical individuals, and reciprocally modulate UBE3A using antisense oligonucleotides. Unbiased proteomics reveal proteins that are regulated by UBE3A in a disease-specific manner, including PEG10, a retrotransposon-derived GAG protein. PEG10 protein increase, but not RNA, is dependent on UBE3A and proteasome function. PEG10 binds to both RNA and ataxia-associated proteins (ATXN2 and ATXN10), localizes to stress granules, and is secreted in extracellular vesicles, modulating vesicle content. Rescue of AS patient-derived neurons by UBE3A reinstatement or PEG10 reduction reveals similarity in transcriptome changes. Overexpression of PEG10 during mouse brain development alters neuronal migration, suggesting that it can affect brain development. These findings imply that PEG10 is a secreted human UBE3A target involved in AS pathophysiology.


Asunto(s)
Síndrome de Angelman/metabolismo , Síndrome de Angelman/fisiopatología , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas de Unión al ADN/metabolismo , Productos del Gen gag/química , Proteínas de Unión al ARN/metabolismo , Retroviridae/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Movimiento Celular , Preescolar , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/ultraestructura , Femenino , Humanos , Células Madre Pluripotentes Inducidas/patología , Masculino , Ratones Endogámicos C57BL , Neuronas/metabolismo , Neuronas/patología , Complejo de la Endopetidasa Proteasomal/metabolismo , Dominios Proteicos , Retroelementos/genética , Gránulos de Estrés/metabolismo , Gránulos de Estrés/ultraestructura , Transcriptoma/genética
6.
Nat Neurosci ; 22(8): 1235-1247, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31235931

RESUMEN

Mutations affecting the gene encoding the ubiquitin ligase UBE3A cause Angelman syndrome. Although most studies focus on the synaptic function of UBE3A, we show that UBE3A is highly enriched in the nucleus of mouse and human neurons. We found that the two major isoforms of UBE3A exhibit highly distinct nuclear versus cytoplasmic subcellular localization. Both isoforms undergo nuclear import through direct binding to PSMD4 (also known as S5A or RPN10), but the amino terminus of the cytoplasmic isoform prevents nuclear retention. Mice lacking the nuclear UBE3A isoform recapitulate the behavioral and electrophysiological phenotypes of Ube3am-/p+ mice, whereas mice harboring a targeted deletion of the cytosolic isoform are unaffected. Finally, we identified Angelman syndrome-associated UBE3A missense mutations that interfere with either nuclear targeting or nuclear retention of UBE3A. Taken together, our findings elucidate the mechanisms underlying the subcellular localization of UBE3A, and indicate that the nuclear UBE3A isoform is the most critical for the pathophysiology of Angelman syndrome.


Asunto(s)
Síndrome de Angelman/genética , Síndrome de Angelman/psicología , Conducta Animal , Ubiquitina-Proteína Ligasas/genética , Animales , Proteínas Portadoras/metabolismo , Núcleo Celular/enzimología , Núcleo Celular/genética , Citosol/enzimología , Fenómenos Electrofisiológicos/genética , Femenino , Humanos , Isoenzimas/genética , Masculino , Ratones , Ratones Noqueados , Mutación Missense/genética , Comportamiento de Nidificación , Neuronas/enzimología , Desempeño Psicomotor , Proteínas de Unión al ARN , Natación/psicología , Dedos de Zinc
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