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1.
Cell ; 151(5): 1097-112, 2012 Nov 21.
Artículo en Inglés | MEDLINE | ID: mdl-23178126

RESUMEN

Microcephaly is a neurodevelopmental disorder causing significantly reduced cerebral cortex size. Many known microcephaly gene products localize to centrosomes, regulating cell fate and proliferation. Here, we identify and characterize a nuclear zinc finger protein, ZNF335/NIF-1, as a causative gene for severe microcephaly, small somatic size, and neonatal death. Znf335 null mice are embryonically lethal, and conditional knockout leads to severely reduced cortical size. RNA-interference and postmortem human studies show that ZNF335 is essential for neural progenitor self-renewal, neurogenesis, and neuronal differentiation. ZNF335 is a component of a vertebrate-specific, trithorax H3K4-methylation complex, directly regulating REST/NRSF, a master regulator of neural gene expression and cell fate, as well as other essential neural-specific genes. Our results reveal ZNF335 as an essential link between H3K4 complexes and REST/NRSF and provide the first direct genetic evidence that this pathway regulates human neurogenesis and neuronal differentiation.


Asunto(s)
Proteínas Portadoras/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Células-Madre Neurales/metabolismo , Neurogénesis , Proteínas Nucleares/metabolismo , Animales , Diferenciación Celular , Proliferación Celular , Proteínas de Unión al ADN , Femenino , Técnicas de Silenciamiento del Gen , Genes Letales , N-Metiltransferasa de Histona-Lisina , Humanos , Masculino , Ratones , Ratones Noqueados , Microcefalia/metabolismo , Complejos Multiproteicos/metabolismo , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Proteínas Represoras/metabolismo , Factores de Transcripción
2.
Nature ; 556(7701): 370-375, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29643508

RESUMEN

The human cerebral cortex is distinguished by its large size and abundant gyrification, or folding. However, the evolutionary mechanisms that drive cortical size and structure are unknown. Although genes that are essential for cortical developmental expansion have been identified from the genetics of human primary microcephaly (a disorder associated with reduced brain size and intellectual disability) 1 , studies of these genes in mice, which have a smooth cortex that is one thousand times smaller than the cortex of humans, have provided limited insight. Mutations in abnormal spindle-like microcephaly-associated (ASPM), the most common recessive microcephaly gene, reduce cortical volume by at least 50% in humans2-4, but have little effect on the brains of mice5-9; this probably reflects evolutionarily divergent functions of ASPM10,11. Here we used genome editing to create a germline knockout of Aspm in the ferret (Mustela putorius furo), a species with a larger, gyrified cortex and greater neural progenitor cell diversity12-14 than mice, and closer protein sequence homology to the human ASPM protein. Aspm knockout ferrets exhibit severe microcephaly (25-40% decreases in brain weight), reflecting reduced cortical surface area without significant change in cortical thickness, as has been found in human patients3,4, suggesting that loss of 'cortical units' has occurred. The cortex of fetal Aspm knockout ferrets displays a very large premature displacement of ventricular radial glial cells to the outer subventricular zone, where many resemble outer radial glia, a subtype of neural progenitor cells that are essentially absent in mice and have been implicated in cerebral cortical expansion in primates12-16. These data suggest an evolutionary mechanism by which ASPM regulates cortical expansion by controlling the affinity of ventricular radial glial cells for the ventricular surface, thus modulating the ratio of ventricular radial glial cells, the most undifferentiated cell type, to outer radial glia, a more differentiated progenitor.


Asunto(s)
Evolución Biológica , Corteza Cerebral/anatomía & histología , Corteza Cerebral/metabolismo , Hurones , Eliminación de Gen , Microcefalia/genética , Microcefalia/patología , Proteínas del Tejido Nervioso/deficiencia , Secuencia de Aminoácidos , Animales , Proteínas de Unión a Calmodulina/deficiencia , Proteínas de Unión a Calmodulina/metabolismo , Centrosoma/metabolismo , Corteza Cerebral/patología , Modelos Animales de Enfermedad , Femenino , Hurones/anatomía & histología , Hurones/genética , Edición Génica , Regulación del Desarrollo de la Expresión Génica , Técnicas de Inactivación de Genes , Mutación de Línea Germinal , Humanos , Masculino , Ratones , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Células-Madre Neurales/metabolismo , Células-Madre Neurales/patología , Tamaño de los Órganos , Transcripción Genética
3.
Genes Dev ; 29(5): 501-12, 2015 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-25737280

RESUMEN

Cellular morphology is an essential determinant of cellular function in all kingdoms of life, yet little is known about how cell shape is controlled. Here we describe a molecular program that controls the early morphology of neurons through a metazoan-specific zinc finger protein, Unkempt. Depletion of Unkempt in mouse embryos disrupts the shape of migrating neurons, while ectopic expression confers neuronal-like morphology to cells of different nonneuronal lineages. We found that Unkempt is a sequence-specific RNA-binding protein and identified its precise binding sites within coding regions of mRNAs linked to protein metabolism and trafficking. RNA binding is required for Unkempt-induced remodeling of cellular shape and is directly coupled to a reduced production of the encoded proteins. These findings link post-transcriptional regulation of gene expression with cellular shape and have general implications for the development and disease of multicellular organisms.


Asunto(s)
Forma de la Célula/genética , Regulación del Desarrollo de la Expresión Génica , Neuronas/citología , Animales , Encéfalo/metabolismo , Línea Celular , Embrión de Mamíferos , Perfilación de la Expresión Génica , Células HeLa , Humanos , Ratones , Unión Proteica , ARN Mensajero
4.
Cereb Cortex ; 27(2): 1670-1685, 2017 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-26826102

RESUMEN

Loss-of-function (LOF) mutations in CC2D1A cause a spectrum of neurodevelopmental disorders, including intellectual disability, autism spectrum disorder, and seizures, identifying a critical role for this gene in cognitive and social development. CC2D1A regulates intracellular signaling processes that are critical for neuronal function, but previous attempts to model the human LOF phenotypes have been prevented by perinatal lethality in Cc2d1a-deficient mice. To overcome this challenge, we generated a floxed Cc2d1a allele for conditional removal of Cc2d1a in the brain using Cre recombinase. While removal of Cc2d1a in neuronal progenitors using Cre expressed from the Nestin promoter still causes death at birth, conditional postnatal removal of Cc2d1a in the forebrain via calcium/calmodulin-dependent protein kinase II-alpha (CamKIIa) promoter-driven Cre generates animals that are viable and fertile with grossly normal anatomy. Analysis of neuronal morphology identified abnormal cortical dendrite organization and a reduction in dendritic spine density. These animals display deficits in neuronal plasticity and in spatial learning and memory that are accompanied by reduced sociability, hyperactivity, anxiety, and excessive grooming. Cc2d1a conditional knockout mice therefore recapitulate features of both cognitive and social impairment caused by human CC2D1A mutation, and represent a model that could provide much needed insights into the developmental mechanisms underlying nonsyndromic neurodevelopmental disorders.


Asunto(s)
Trastorno del Espectro Autista/genética , Discapacidad Intelectual/genética , Neuronas/citología , Prosencéfalo/patología , Proteínas Represoras/metabolismo , Animales , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Dendritas/metabolismo , Dendritas/patología , Modelos Animales de Enfermedad , Humanos , Ratones Transgénicos , Plasticidad Neuronal/genética , Proteínas Represoras/deficiencia , Transducción de Señal/fisiología
5.
Neuron ; 109(20): 3239-3251.e7, 2021 10 20.
Artículo en Inglés | MEDLINE | ID: mdl-34478631

RESUMEN

Human accelerated regions (HARs) are the fastest-evolving regions of the human genome, and many are hypothesized to function as regulatory elements that drive human-specific gene regulatory programs. We interrogate the in vitro enhancer activity and in vivo epigenetic landscape of more than 3,100 HARs during human neurodevelopment, demonstrating that many HARs appear to act as neurodevelopmental enhancers and that sequence divergence at HARs has largely augmented their neuronal enhancer activity. Furthermore, we demonstrate PPP1R17 to be a putative HAR-regulated gene that has undergone remarkable rewiring of its cell type and developmental expression patterns between non-primates and primates and between non-human primates and humans. Finally, we show that PPP1R17 slows neural progenitor cell cycle progression, paralleling the cell cycle length increase seen predominantly in primate and especially human neurodevelopment. Our findings establish HARs as key components in rewiring human-specific neurodevelopmental gene regulatory programs and provide an integrated resource to study enhancer activity of specific HARs.


Asunto(s)
Encéfalo/embriología , Regulación del Desarrollo de la Expresión Génica/genética , Redes Reguladoras de Genes/genética , Animales , Evolución Biológica , Epigenómica , Evolución Molecular , Hurones , Humanos , Macaca , Ratones , Pan troglodytes
6.
Neuron ; 106(2): 246-255.e6, 2020 04 22.
Artículo en Inglés | MEDLINE | ID: mdl-32097629

RESUMEN

Genes mutated in human neuronal migration disorders encode tubulin proteins and a variety of tubulin-binding and -regulating proteins, but it is very poorly understood how these proteins function together to coordinate migration. Additionally, the way in which regional differences in neocortical migration are controlled is completely unknown. Here we describe a new syndrome with remarkably region-specific effects on neuronal migration in the posterior cortex, reflecting de novo variants in CEP85L. We show that CEP85L is required cell autonomously in vivo and in vitro for migration, that it localizes to the maternal centriole, and that it forms a complex with many other proteins required for migration, including CDK5, LIS1, NDE1, KIF2A, and DYNC1H1. Loss of CEP85L disrupts CDK5 localization and activation, leading to centrosome disorganization and disrupted microtubule cytoskeleton organization. Together, our findings suggest that CEP85L highlights a complex that controls CDK5 activity to promote neuronal migration.


Asunto(s)
Movimiento Celular , Quinasa 5 Dependiente de la Ciclina/genética , Proteínas del Citoesqueleto/genética , Lisencefalia/genética , Lisencefalia/patología , Neocórtex/patología , Neuronas/patología , Proteínas de Fusión Oncogénica/genética , Centriolos/genética , Niño , Preescolar , Femenino , Humanos , Masculino , Microtúbulos/genética , Microtúbulos/ultraestructura , Proteínas del Tejido Nervioso/fisiología , Adulto Joven
7.
Cell Rep ; 24(4): 973-986.e8, 2018 07 24.
Artículo en Inglés | MEDLINE | ID: mdl-30044992

RESUMEN

Endosomal sorting complex required for transport (ESCRT) complex proteins regulate biogenesis and release of extracellular vesicles (EVs), which enable cell-to-cell communication in the nervous system essential for development and adult function. We recently showed human loss-of-function (LOF) mutations in ESCRT-III member CHMP1A cause autosomal recessive microcephaly with pontocerebellar hypoplasia, but its mechanism was unclear. Here, we show Chmp1a is required for progenitor proliferation in mouse cortex and cerebellum and progenitor maintenance in human cerebral organoids. In Chmp1a null mice, this defect is associated with impaired sonic hedgehog (Shh) secretion and intraluminal vesicle (ILV) formation in multivesicular bodies (MVBs). Furthermore, we show CHMP1A is important for release of an EV subtype that contains AXL, RAB18, and TMED10 (ART) and SHH. Our findings show CHMP1A loss impairs secretion of SHH on ART-EVs, providing molecular mechanistic insights into the role of ESCRT proteins and EVs in the brain.


Asunto(s)
Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Vesículas Extracelulares/metabolismo , Proteínas Hedgehog/metabolismo , Adulto , Animales , Encéfalo/embriología , Encéfalo/metabolismo , Plexo Coroideo/embriología , Plexo Coroideo/crecimiento & desarrollo , Plexo Coroideo/metabolismo , Humanos , Recién Nacido , Ratones , Células 3T3 NIH , Proteínas de Transporte Vesicular
8.
Neuron ; 92(4): 813-828, 2016 Nov 23.
Artículo en Inglés | MEDLINE | ID: mdl-27974163

RESUMEN

Mutations in several genes encoding centrosomal proteins dramatically decrease the size of the human brain. We show that Aspm (abnormal spindle-like, microcephaly-associated) and Wdr62 (WD repeat-containing protein 62) interact genetically to control brain size, with mice lacking Wdr62, Aspm, or both showing gene dose-related centriole duplication defects that parallel the severity of the microcephaly and increased ectopic basal progenitors, suggesting premature delamination from the ventricular zone. Wdr62 and Aspm localize to the proximal end of the mother centriole and interact physically, with Wdr62 required for Aspm localization, and both proteins, as well as microcephaly protein Cep63, required to localize CENPJ/CPAP/Sas-4, a final common target. Unexpectedly, Aspm and Wdr62 are required for normal apical complex localization and apical epithelial structure, providing a plausible unifying mechanism for the premature delamination and precocious differentiation of progenitors. Together, our results reveal links among centrioles, apical proteins, and cell fate, and illuminate how alterations in these interactions can dynamically regulate brain size.


Asunto(s)
Encéfalo/embriología , Proteínas de Unión a Calmodulina/genética , Proteínas de Ciclo Celular/genética , Diferenciación Celular/genética , Centriolos/metabolismo , Microcefalia/genética , Proteínas Asociadas a Microtúbulos/genética , Proteínas del Tejido Nervioso/genética , Biogénesis de Organelos , Animales , Western Blotting , Encéfalo/metabolismo , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Inmunoprecipitación , Espectrometría de Masas , Ratones , Células Madre Embrionarias de Ratones , Mutación
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