Single-Cell Transcriptomics Analyses of Neural Stem Cell Heterogeneity and Contextual Plasticity in a Zebrafish Brain Model of Amyloid Toxicity

Coşacak, Mehmet İlyas; Bhattarai, Prabesh; Reinhardt, Susanne; Petzold, A.; Dahl, Andreas; Zhang, Yixin; Kızıl, Çağhan

doi:10.1016/j.celrep.2019.03.090

Cited by 99 publications

(174 citation statements)

References 79 publications

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“…We hypothesized that a possible regulation between htr1+ neurons and NSCs could be through a paracrine ligand-receptor crosstalk. We found that in htr1+ cells, 29 ligands change their expression levels ( Figure 3C), five of which also change their expression reciprocally after 5-HT or IL4 treatment ( Figure 3D, and data from (Cosacak et al, 2019)). The highest fold change was observed for bdnf, which is enhanced by IL4 and downregulated by 5-HT ( Figure 3D).…”

Section: Resultsmentioning

confidence: 78%

“…Our previous results indicated that a subset of NSCs express IL4 receptor and can therefore be directly regulated by IL4 Cosacak et al, 2019). Therefore, we aimed to investigate if 5-HT would affect the same subset of NSCs or whether it affects a distinct population.…”

Section: Resultsmentioning

confidence: 99%

“…To determine the mechanistic link between 5-HT and NSC plasticity through hrt1+ cells ( Figure 2P), we performed single cell transciptomics in control and 5-HT-treated adult zebrafish telencephalon by unbiased clustering, determination of cell types and differential gene expression analyses using the methodology we have recently developed (Cosacak et al, 2019;Cosacak et al, 2018) (FigureS3A;Dataset S3). After quality control analyses ( Figure S3B), we obtained tSNE clusters, which dissolve into four major cell types: neurons (eno2, gap43, map1aa, sypb-positive), glia (gfap, her4.1, msi1, s100b-positive); oligodendrocytes (aplnrb, olig2-positive) and immune cells (pfn, lcp1-positive) ( Figure S3C-E).…”

Section: Resultsmentioning

confidence: 99%

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Neuron-glia interaction through Serotonin-BDNF-NGFR axis enables regenerative neurogenesis in Alzheimer’s model of adult zebrafish brain

Bhattarai

Coşacak

Mashkaryan

et al. 2019

Preprint

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It was recently suggested that supplying the brain with new neurons could counteract Alzheimer's disease. This provocative idea requires further testing in experimental models where the molecular basis of disease-induced neuronal regeneration could be investigated. We previously found that zebrafish stimulates neural stem cell (NSC) plasticity and neurogenesis in Alzheimer's disease and could help to understand the mechanisms to be harnessed for develop new neurons in diseased mammalian brains. Here, by performing singlecell transcriptomics, we found that Amyloid toxicity-induced Interleukin-4 induces NSC proliferation and neurogenesis by suppressing the tryptophan metabolism and reducing the production of Serotonin. NSC proliferation was suppressed by Serotonin via downregulation of BDNF-expression in Serotoninresponsive periventricular neurons. BDNF enhances NSC plasticity and neurogenesis via NGFRA/NFkB signaling in zebrafish but not in rodents. Collectively, our results suggest a complex neuron-glia interaction that regulates regenerative neurogenesis after Alzheimer's disease conditions in zebrafish. Key findings-Amyloid-induced Interleukin-4 suppresses Serotonin (5-HT) production in adult zebrafish brain -5-HT affects htr1-expresing neurons and suppresses bdnf expression -BDNF enhances plasticity in neural stem cells via NGFRA/NFkB signaling -BDNF/NGFRA signaling is a neuro-regenerative mechanism in zebrafish but not in mammals.

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Section: Resultsmentioning

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Neuron-glia interaction through Serotonin-BDNF-NGFR axis enables regenerative neurogenesis in Alzheimer’s model of adult zebrafish brain

Bhattarai

Coşacak

Mashkaryan

et al. 2019

Preprint

Self Cite

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“…Recently, zebrafish telencephalic stem cells were investigated with a transcriptomic approach (Cosacak et al, 2019) and shown to be organized into molecularly separable populations that are clearly closely correlated with earlier established neuroanatomical divisions (Wullimann et al, 1996). One of these stem cell populations is in the medial zone of the pallial telencephalon (Dm; considered the pallial amygdala; Portavella et al, 2002Portavella et al, , 2004Wullimann & Mueller, 2004;Lal et al, 2018) which is characterized by marker genes pou3f1 and dmrta2 (Cosacak et al, 2019). It appears that we show here with shh-GFP specifically this population of molecularly defined radial glia cells within the medial zone of the dorsal (pallial) telencephalon (Dm; Figure 1).…”

Section: Pallial Shh-gfp Radial Glia Cells In Medial Zone Of Dorsalmentioning

confidence: 99%

Sonic hedgehog expression in zebrafish forebrain identifies the teleostean pallidal signaling center and shows preglomerular complex and posterior tubercular dopamine cells to arise from shh cells

Wullimann

Umeasalugo

2019

J of Comparative Neurology

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Ventralization, a major patterning process in the developing vertebrate neural tube (central nervous system, CNS), depends on Sonic hedgehog (SHH) as a main signaling morphogen. We studied the CNS of late larval and young adult zebrafish in a transgenic shh‐GFP line revealing increased neuroanatomical detail due to the progressed differentiation state compared to earlier stages. Some major findings emerge from the present study. (a) shh –GFP is still expressed along the adult zebrafish CNS neuraxis in most locations seen in larvae. (b) We newly identify a ventroposterior shh pallidal domain representing the basal telencephalic signaling center important for basal ganglia development known in other vertebrates (i.e., the anterior entopeduncular area—basal medial ganglionic eminence of mammals). (c) We further show late‐emerging shh‐GFP positive radial glia cells in the medial zone of the dorsal telencephalon (i.e., the teleostan pallial amygdala). (d) Immunostains for tyrosine hydroxylase demonstrate that there is selective colocalization in adult dopamine cells with shh‐GFP in the posterior tuberculum, including in projection cells to striatum, which represents a striking parallel to amniote mesodiencephalic dopamine cell origin from shh expressing floor plate cells. (e) There is no colocalization of shh and islet1 as shown by respective shh‐GFP and islet1‐GFP lines. (f) The only radially far migrated shh‐GFP cells are located in the preglomerular area. (g) There are no adult cerebellar and tectal shh‐GFP cells confirming their exclusive role during early development as previously reported by our laboratory.

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“…Briefly, olfactory projection neuron, aging brain, and midbrain were analyzed to understand neural cell subtypes [37]. In zebrafish, scRNA-seq was used to dissect cellular lineages and cell types in both brains from healthy and amyloid toxicity model [38]. Pig brain has been investigated in the apsects of genome, transcriptome and epigenome, establishing a basic preception structurally and functionally [24,39].…”

mentioning

confidence: 99%

Single cell atlas of domestic pig brain illuminates the conservation and divergence of cell types at spatial and species levels

Chen

Zhu

Zhong

et al. 2019

Preprint

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Domestic pig (Sus scrofa domesticus) has drawn much attention from researchers worldwide due to its implications in evolutionary biology, regenerative medicine and agriculture. The brain atlas of Homo sapiens (primate), Mus musculus (rodent), Danio rerio (fish) and Drosophila melanogaster (insect) have been constructed at single cell resolution, however, the cellular compositions of pig brain remain largely unexplored. In this study, we investigated the single-cell transcriptomic profiles of five distinct regions of domestic pig brain, from which we identified 21 clusters corresponding to six major cell types, characterized by unique spectrum of gene expression. By spatial comparison, we identified cell types enriched or depleted in certain brain regions. Inter-species comparison revealed cell-type similarities and divergences in hypothalamus between mouse and pig, providing invaluable resources for the evolutionary exploration of brain functions at single cell level. Besides, our study revealed cell types and molecular pathways closely associated with several diseases (obesity, anorexia, bulimia, epilepsy, intellectual disability, and autism spectrum disorder), bridging the gap between gene mutations and pathological phenotypes, which might be of great use to the development precise therapies against neural system disorders. Taken together, we reported, so far as we know, the first single cell brain atlas of Sus scrofa domesticus, followed by comprehensive comparisons across brain region and species, which could throw light upon future evo-devo, regenerative medicine, and agricultural studies. Introduction:The domestic pig (Sus scrofa domesticus), one of the most important livestocks, shares close interaction relationships with humans during evolution history [1][2][3]. It belongs to the eutherian mammal from cetartiodactyla order, a clade distinct from primates and rodents [4]. Domestic pig has been widely studied because of its significances in evolutionary biology and regenerative medicine [5]. During the past decades, pig is increasingly used in neuroscience researches, due to the much higher correspondence in its brain to human brain in anatomy, physiology, and development than that of commonly used small laboratory animals such as mouse and rat [6,7]. Similar to human brain, pig brain is gyrencephalic and easy to recognize anatomically. For example, the cerebral cortex is clearly differentiated into four lobes including temporal lobe (TL), frontal lobe (FL), parital lobe (PL), and occipital lobe (OL) [8]. Recently, a transgenetic pig Huntington's disease (HD) model was established by a mutant huntingtin knockin, who shows classical HD phenotypes such as behavioral abnormalities, consistent movement and early death [9]. Accumulating genetic manipulation tools have facilitated the applications of pig as an animal model for researches into brain function, particularly studies concerning brain malfunctioning mechanism. Besides, for ethical and economical reasons, pig is a more acceptable lab animal than primat...

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Single-Cell Transcriptomics Analyses of Neural Stem Cell Heterogeneity and Contextual Plasticity in a Zebrafish Brain Model of Amyloid Toxicity

Cited by 99 publications

References 79 publications

Neuron-glia interaction through Serotonin-BDNF-NGFR axis enables regenerative neurogenesis in Alzheimer’s model of adult zebrafish brain

Neuron-glia interaction through Serotonin-BDNF-NGFR axis enables regenerative neurogenesis in Alzheimer’s model of adult zebrafish brain

Sonic hedgehog expression in zebrafish forebrain identifies the teleostean pallidal signaling center and shows preglomerular complex and posterior tubercular dopamine cells to arise from shh cells

Single cell atlas of domestic pig brain illuminates the conservation and divergence of cell types at spatial and species levels

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