Spatiotemporal gene expression trajectories reveal developmental hierarchies of the human cortex

By T. Nowakowski, A. Bhaduri, Alex A. Pollen, Beatriz Alvarado, M. Mostajo-Radji, Elizabeth Di Lullo, Maximilian Haeussler, Carmen Sandoval-Espinosa, S. Liu, Dmitry Velmeshev and 8 more. Science, 2017

867 citations recorded by the source corpus.

Building a brain The human brain is built in an inside-out manner as a series of layers. Although progenitor cells spin off new neurons in a seemingly organized fashion, the devil is in the details. Nowakowski et al. analyzed the transcriptomes of single cells from the developing brain to elucidate the hidden complexity of brain construction. For each cell, its position within the brain matters, as well as what type of neuron is being made at what point during overall development. These individual expression patterns result in organized diversity in the brain's cortex. Science, this issue p. 1318 Location, type, and time all cooperate to diversify individual progenitors and neurons of the developing human brain. Systematic analyses of spatiotemporal gene expression trajectories during organogenesis have been challenging because diverse cell types at different stages of maturation and differentiation coexist in the emerging tissues. We identified discrete cell types as well as temporally and spatially restricted trajectories of radial glia maturation and neurogenesis in developing human telencephalon. These lineage-specific trajectories reveal the expression of neurogenic transcription factors in early radial glia and enriched activation of mammalian target of rapamycin signaling in outer radial glia. Across cortical areas, modest transcriptional differences among radial glia cascade into robust typological distinctions among maturing neurons. Together, our results support a mixed model of topographical, typological, and temporal hierarchies governing cell-type diversity in the developing human telencephalon, including distinct excitatory lineages emerging in rostral and caudal cerebral cortex.

Subfields: Developmental Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/f6dfb471168febb2c0e2eeb9f9852360047e19ae

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Citations in the corpus

An integrative model of cellular states, plasticity and genetics for glioblastoma (2019, neutral): “(2) Second, by the global expression similarities (Pearson correlations) between 47 non-malignant cell types in the developing human cortex (Nowakowski et al., 2017) and the average profiles of 250 randomly sampled glioblastoma cells mapping to each of the metamodules (Figure S2F).”
Transcriptome-scale spatial gene expression in the human dorsolateral prefrontal cortex (2020, background): “…increased identification of molecularly-defined cell types in the human brain and implicated unique cell classes in risk for specific brain disorders (Darmanis et al., 2015; Hodge et al., 2019; Lake et al., 2016, 2018; Mathys et al., 2019; Nowakowski et al., 2017; Velmeshev et al., 2019).”
Comprehensive analysis of retinal development at single cell resolution identifies NFI factors as essential for mitotic exit and specification of late-born cells (2018, background): “The authors would like to few thousand cells, usually at a relatively smaller number of developmental ages (La Manno et al., 2016; Mayer et al., 2018; Nowakowski et al., 2017; Zhong et al., 2018), and thus do not fully capture the transcriptional changes associated with the initiation of neurogenesi”
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism (2019, methodology): “(D) The cumulative number of ASD-associated genes expressed in RNA-seq dat (Nowakowski et al., 2017).”
Integrative functional genomic analysis of human brain development and neuropsychiatric risks (2018, methodology): “Demonstrating the robustness of these observations, independent deconvolution using two alternate fetal single-cell datasets (12, 26) yielded similar results (figs.”