A Taxonomy of Transcriptomic Cell Types Across the Isocortex and Hippocampal Formation

Yao, Zizhen; Nguyen, Thuc Nghi; Velthoven, Cindy T. J. van; Goldy, Jeff; Sedeño-Cortés, Adriana E.; Baftizadeh, Fahimeh; Bertagnolli, Darren; Casper, Tamara; Crichton, Kirsten; Ding, Shilei; Fong, Olivia; Garren, Emma; Glandon, Alexandra; Gray, J.; Graybuck, Lucas T.; Hawrylycz, Michael; Hirschstein, Daniel; Kroll, Matthew; Lathia, Kanan; McMillen, Delissa; Mok, Stéphanie; Pham, Thanh; Ren, Qingzhong; Rimorin, Christine; Shapovalova, Nadiya V.; Šulc, Josef; Sunkin, Susan M.; Tieu, Michael; Torkelson, Amy; Tung, Herman; Ward, Katelyn; Dee, Nick; Smith, Kimberly A.; Tasic, Bosiljka; Zeng, Hongkui

doi:10.2139/ssrn.3575167

Cited by 141 publications

(299 citation statements)

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“…We found out that the two clusters of medial CRs (Trp73 + ) can be distinguished by the opposite expression of gene modules correlating with spatial positioning of neurons along the DV axis, consistent with the hypothesis that part of CR identity is imposed by the environment in which they settle. Such a spatial component to neuronal identity has also recently been highlighted for pyramidal neurons of the neocortex (Yao and Tasic, 2020).…”

Section: Discussionmentioning

confidence: 86%

Single-cell transcriptomics of the early developing mouse cerebral cortex disentangles the spatial and temporal components of neuronal fate acquisition

Moreau

Saillour

Cwetsch

et al. 2020

Preprint

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In the developing cerebral cortex, how progenitors that seemingly display limited diversity end up in producing a vast array of neurons remains a puzzling question. The prevailing model that recently emerged suggests that temporal maturation of these progenitors is a key driver in the diversification of the neuronal output. However, temporal constrains are unlikely to account for all diversity across cortical regions, especially in the ventral and lateral domains where neuronal types significantly differ from their dorsal neocortical counterparts born at the same time. In this study, we implemented single-cell RNAseq to sample the diversity of progenitors and neurons along the dorso-ventral axis of the early developing pallium. We first identified neuronal types, mapped them on the tissue and performed genetic tracing to determine their origin. By characterising progenitor diversity, we disentangled the gene expression modules underlying temporal vs spatial regulations of neuronal specification. Finally, we reconstructed the developmental trajectories followed by ventral and dorsal pallial neurons to identify gene waves specific of each lineage. Our data suggest a model by which discrete neuronal fate acquisition from a continuous gradient of progenitors results from the superimposition of spatial information and temporal maturation.

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Section: Discussionmentioning

confidence: 86%

Single-cell transcriptomics of the early developing mouse cerebral cortex disentangles the spatial and temporal components of neuronal fate acquisition

Moreau

Saillour

Cwetsch

et al. 2020

Preprint

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“…The identities of clusters 12, 13, 16, 17 are matched with the top gene markers identified by the FindAllMarkers(). These four clusters are Gad1 +, Pvalb + and Vip -, and were putatively annotated as Bistratified, Fast-spiking, and Axo-axonic subsets of PV+INTs, based on marker expression of Sst , Tac1 , and Pthlh , respectively, as indicated in interneuron literature and previous scRNAseq studies ( Fishell and Kepecs, 2020 ; Hodge et al, 2019 ; Paul et al, 2017 ; Pelkey et al, 2017 ; Saunders et al, 2018 ; Tasic et al, 2016 ; Tasic et al, 2018 ; Yao et al, 2020 ; Harris et al, 2018 ). Subsequent to dataset validation using references, the Pafah1b1 +/+ and Pafah1b1 +/- datasets reanalyzed by subsetting the cells that expressed Gad1 , Pvalb expression >0.1 and by excluding the cells containing non-PV+INT genes Slc17a7 , Ttr , Scn3a , Gpc5 , Slc1a2, Htr2c , Trpm3 expressions < 0.1.…”

Section: Methodsmentioning

confidence: 84%

“…Single-cell transcriptomes from Nkx2.1-cre:Ai14, MGE-derived cortical and hippocampal interneurons (postnatal day 18-20) were processed as previously described (Mahadevan et al, 2020). To perform integrated analyses, we identified a common set of genes between Pafah1b1 +/+ , Pafah1b1 +/-, Nkx2.1-MGE cortical and hippocampal interneurons and Allen datasets, and utilized these for the initial analyses in Figure 7-figure supplements 1 (Fishell and Kepecs, 2020;Hodge et al, 2019;Paul et al, 2017;Pelkey et al, 2017;Saunders et al, 2018;Tasic et al, 2016Tasic et al, , 2018Yao et al, 2020;Harris et al, 2018).…”

Section: Rnaseq Data Processing and Analyses Differential Expression Tmentioning

confidence: 99%

Emergence of non-canonical parvalbumin-containing interneurons in hippocampus of a murine model of type I lissencephaly

Ekins

Mahadevan

Zhang

et al. 2020

eLife

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Type I lissencephaly is a neuronal migration disorder caused by haploinsuffiency of the PAFAH1B1 (mouse: Pafah1b1) gene and is characterized by brain malformation, developmental delays, and epilepsy. Here, we investigate the impact of Pafah1b1 mutation on the cellular migration, morphophysiology, microcircuitry and transcriptomics of mouse hippocampal CA1 parvalbumin-containing inhibitory interneurons (PV+INTs). We find that WT PV+INTs consist of two physiological subtypes (80% fast-spiking (FS), 20% non-fast-spiking (NFS)) and four morphological subtypes. We find that cell-autonomous mutations within interneurons disrupts morphophysiological development of PV+INTs and results in the emergence of a non-canonical 'intermediate spiking (IS)' subset of PV+INTs. We also find that now dominant IS/NFS cells are prone to entering depolarization block, causing them to temporarily lose the ability to initiate action potentials and control network excitation, potentially promoting seizures. Finally, single-cell nuclear RNAsequencing of PV+INTs revealed several misregulated genes related to morphogenesis, cellular excitability, and synapse formation.

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“…Clusterin is expressed in many cell types throughout the body, most notably in specialized secretory cells and epithelial cells ( Aronow et al, 1993 ). Within the brain, clusterin is ubiquitously expressed in neurons and glia, and is especially abundant in astrocytes, while being absent from microglia ( Yao et al, 2020 ) 1 . Circulating clusterin levels are very high in serum, predominantly derived from the liver ( Seo et al, 2020 ), and approximate 100 μg/ml (about 1.6 μM).…”

Section: Clusterinmentioning

confidence: 99%

Secreted Chaperones in Neurodegeneration

Chaplot

Jarvela

Lindberg

2020

Front. Aging Neurosci.

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Protein homeostasis, or proteostasis, is a combination of cellular processes that govern protein quality control, namely, protein translation, folding, processing, and degradation. Disruptions in these processes can lead to protein misfolding and aggregation. Proteostatic disruption can lead to cellular changes such as endoplasmic reticulum or oxidative stress; organelle dysfunction; and, if continued, to cell death. A majority of neurodegenerative diseases involve the pathologic aggregation of proteins that subverts normal neuronal function. While prior reviews of neuronal proteostasis in neurodegenerative processes have focused on cytoplasmic chaperones, there is increasing evidence that chaperones secreted both by neurons and other brain cells in the extracellular – including transsynaptic – space play important roles in neuronal proteostasis. In this review, we will introduce various secreted chaperones involved in neurodegeneration. We begin with clusterin and discuss its identification in various protein aggregates, and the use of increased cerebrospinal fluid (CSF) clusterin as a potential biomarker and as a potential therapeutic. Our next secreted chaperone is progranulin; polymorphisms in this gene represent a known genetic risk factor for frontotemporal lobar degeneration, and progranulin overexpression has been found to be effective in reducing Alzheimer’s- and Parkinson’s-like neurodegenerative phenotypes in mouse models. We move on to BRICHOS domain-containing proteins, a family of proteins containing highly potent anti-amyloidogenic activity; we summarize studies describing the biochemical mechanisms by which recombinant BRICHOS protein might serve as a therapeutic agent. The next section of the review is devoted to the secreted chaperones 7B2 and proSAAS, small neuronal proteins which are packaged together with neuropeptides and released during synaptic activity. Since proteins can be secreted by both classical secretory and non-classical mechanisms, we also review the small heat shock proteins (sHsps) that can be secreted from the cytoplasm to the extracellular environment and provide evidence for their involvement in extracellular proteostasis and neuroprotection. Our goal in this review focusing on extracellular chaperones in neurodegenerative disease is to summarize the most recent literature relating to neurodegeneration for each secreted chaperone; to identify any common mechanisms; and to point out areas of similarity as well as differences between the secreted chaperones identified to date.

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A Taxonomy of Transcriptomic Cell Types Across the Isocortex and Hippocampal Formation

Cited by 141 publications

References 0 publications

Single-cell transcriptomics of the early developing mouse cerebral cortex disentangles the spatial and temporal components of neuronal fate acquisition

Single-cell transcriptomics of the early developing mouse cerebral cortex disentangles the spatial and temporal components of neuronal fate acquisition

Emergence of non-canonical parvalbumin-containing interneurons in hippocampus of a murine model of type I lissencephaly

Secreted Chaperones in Neurodegeneration

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