RESUMEN
The transcriptional underpinnings of brain development remain poorly understood, particularly in humans and closely related non-human primates. We describe a high-resolution transcriptional atlas of rhesus monkey (Macaca mulatta) brain development that combines dense temporal sampling of prenatal and postnatal periods with fine anatomical division of cortical and subcortical regions associated with human neuropsychiatric disease. Gene expression changes more rapidly before birth, both in progenitor cells and maturing neurons. Cortical layers and areas acquire adult-like molecular profiles surprisingly late in postnatal development. Disparate cell populations exhibit distinct developmental timing of gene expression, but also unexpected synchrony of processes underlying neural circuit construction including cell projection and adhesion. Candidate risk genes for neurodevelopmental disorders including primary microcephaly, autism spectrum disorder, intellectual disability, and schizophrenia show disease-specific spatiotemporal enrichment within developing neocortex. Human developmental expression trajectories are more similar to monkey than rodent, although approximately 9% of genes show human-specific regulation with evidence for prolonged maturation or neoteny compared to monkey.
Asunto(s)
Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Macaca mulatta/genética , Transcriptoma , Envejecimiento/genética , Animales , Trastorno del Espectro Autista/genética , Encéfalo/citología , Encéfalo/embriología , Adhesión Celular , Secuencia Conservada , Femenino , Humanos , Discapacidad Intelectual/genética , Masculino , Microcefalia/genética , Neocórtex/embriología , Neocórtex/crecimiento & desarrollo , Neocórtex/metabolismo , Trastornos del Neurodesarrollo/genética , Neurogénesis/genética , Factores de Riesgo , Esquizofrenia/genética , Análisis Espacio-Temporal , Especificidad de la Especie , Transcripción Genética/genéticaRESUMEN
The anatomical and functional architecture of the human brain is mainly determined by prenatal transcriptional processes. We describe an anatomically comprehensive atlas of the mid-gestational human brain, including de novo reference atlases, in situ hybridization, ultra-high-resolution magnetic resonance imaging (MRI) and microarray analysis on highly discrete laser-microdissected brain regions. In developing cerebral cortex, transcriptional differences are found between different proliferative and post-mitotic layers, wherein laminar signatures reflect cellular composition and developmental processes. Cytoarchitectural differences between human and mouse have molecular correlates, including species differences in gene expression in subplate, although surprisingly we find minimal differences between the inner and outer subventricular zones even though the outer zone is expanded in humans. Both germinal and post-mitotic cortical layers exhibit fronto-temporal gradients, with particular enrichment in the frontal lobe. Finally, many neurodevelopmental disorder and human-evolution-related genes show patterned expression, potentially underlying unique features of human cortical formation. These data provide a rich, freely-accessible resource for understanding human brain development.
Asunto(s)
Encéfalo/metabolismo , Feto/metabolismo , Regulación del Desarrollo de la Expresión Génica/genética , Transcriptoma , Anatomía Artística , Animales , Atlas como Asunto , Encéfalo/embriología , Secuencia Conservada/genética , Feto/citología , Feto/embriología , Redes Reguladoras de Genes/genética , Humanos , Ratones , Neocórtex/embriología , Neocórtex/metabolismo , Especificidad de la EspecieRESUMEN
Glioblastoma is an aggressive brain tumor that carries a poor prognosis. The tumor's molecular and cellular landscapes are complex, and their relationships to histologic features routinely used for diagnosis are unclear. We present the Ivy Glioblastoma Atlas, an anatomically based transcriptional atlas of human glioblastoma that aligns individual histologic features with genomic alterations and gene expression patterns, thus assigning molecular information to the most important morphologic hallmarks of the tumor. The atlas and its clinical and genomic database are freely accessible online data resources that will serve as a valuable platform for future investigations of glioblastoma pathogenesis, diagnosis, and treatment.