Cell type-specific epigenetic links to schizophrenia risk in the brain

Isolation and proteomic profiling of brain cell types, particularly neurons, pose several technical challenges which limit our ability to resolve distinct cellular phenotypes in neurological diseases. Therefore, we generated a novel mouse line that enables cell type-specific expression of a biotin ligase, TurboID, via Cre-lox strategy for in vivo proximity-dependent biotinylation of proteins. Using adenoviral-based and transgenic approaches, we show striking protein biotinylation in neuronal cell bodies and axons throughout the mouse brain. We quantified more than 2,000 neuron-derived proteins following enrichment that mapped to numerous subcellular compartments. Synaptic, transmembrane transporters, ion channel subunits, and disease-relevant druggable targets were among the most significantly enriched proteins. Remarkably, we resolved brain region-specific proteomic profiles of Camk2a neurons with distinct functional molecular signatures and disease associations that may underlie regional neuronal vulnerability. Leveraging the neuronal specificity of this in vivo biotinylation strategy, we used an antibody-based approach to uncover regionally unique patterns of neuron-derived signaling phospho-proteins and cytokines, particularly in the cortex and cerebellum. Our work provides a proteomic framework to investigate cell type-specific mechanisms driving physiological and pathological states of the brain as well as complex tissues beyond the brain.

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Light Up the Brain: The Application of Optogenetics in Cell-Type Specific Dissection of Mouse Brain Circuits

Frontiers in Neural Circuits ◽

10.3389/fncir.2020.00018 ◽

2020 ◽

Vol 14 ◽

Cited By ~ 1

Author(s):

Candice Lee ◽

Andreanne Lavoie ◽

Jiashu Liu ◽

Simon X. Chen ◽

Bao-hua Liu

Keyword(s):

Mouse Brain ◽

Cell Type ◽

Brain Circuits ◽

Cell Type Specific ◽

The Brain

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Cell Type Specific Expression of Toll-Like Receptors in Human Brains and Implications in Alzheimer’s Disease

BioMed Research International ◽

10.1155/2019/7420189 ◽

2019 ◽

Vol 2019 ◽

pp. 1-18 ◽

Cited By ~ 10

Author(s):

Henriette R. Frederiksen ◽

Henriette Haukedal ◽

Kristine Freude

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cellular Response ◽

The Body ◽

Cellular Damage ◽

Whole Body ◽

Toll Like Receptors ◽

Cell Type ◽

Cell Type Specific ◽

The Brain

Toll-like receptors mediate important cellular immune responses upon activation via various pathogenic stimuli such as bacterial or viral components. The activation and subsequent secretion of cytokines and proinflammatory factors occurs in the whole body including the brain. The subsequent inflammatory response is crucial for the immune system to clear the pathogen(s) from the body via the innate and adaptive immune response. Within the brain, astrocytes, neurons, microglia, and oligodendrocytes all bear unique compositions of Toll-like receptors. Besides pathogens, cellular damage and abnormally folded protein aggregates, such as tau and Amyloid beta peptides, have been shown to activate Toll-like receptors in neurodegenerative diseases such as Alzheimer’s disease. This review provides an overview of the different cell type-specific Toll-like receptors of the human brain, their activation mode, and subsequent cellular response, as well as their activation in Alzheimer’s disease. Finally, we critically evaluate the therapeutic potential of targeting Toll-like receptors for treatment of Alzheimer’s disease as well as discussing the limitation of mouse models in understanding Toll-like receptor function in general and in Alzheimer’s disease.

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The appearance of neural and glial cell markers during early development of the nervous system in the amphibian embryo

Development ◽

10.1242/dev.107.1.43 ◽

1989 ◽

Vol 107 (1) ◽

pp. 43-54 ◽

Cited By ~ 1

Author(s):

N.J. Messenger ◽

A.E. Warner

Keyword(s):

Nervous System ◽

Glial Cell ◽

Glial Cells ◽

Cell Type ◽

Neurofilament Protein ◽

Amphibian Embryo ◽

Specific Antibodies ◽

Cell Type Specific ◽

Radial Glial ◽

The Brain

Cell-type-specific antibodies have been used to follow the appearance of neurones and glia in the developing nervous system of the amphibian embryo. Differentiated neurones were recognized with antibodies against neurofilament protein while glial cells were identified with antibodies against glial fibrillary acidic protein (GFAP). The appearance of neurones containing the neurotransmitters 5-hydroxytryptamine and dopamine has been charted also. In Xenopus, neurofilament protein in developing neurones was observed occasionally at NF stage 21 and was present reliably in the neural tube and in caudal regions of the brain at stage 23. Antibodies to the low molecular weight fragment of the neurofilament triplet recognized early neurones most reliably. Radial glial cells, identified with GFAP antibody, were identified from stage 23 onwards in the neural tube and caudal regions of the brain. In the developing spinal cord, GFAP staining was apparent throughout the cytoplasm of each radial glial cell. In the brain, the peripheral region only of each glial cell contained GFAP. By stage 36, immunohistochemically recognizable neurones and glia were present throughout the nervous system. In the axolotl, by stage 36 the pattern of neural and glial staining was identical to that observed in Xenopus. GFAP staining of glial cells was obvious at stage 23, although neuronal staining was clearly absent. This implies that glial cells differentiate before neurones. 5-HT-containing cell bodies were first observed in caudal regions of the developing brain on either side of the midline at stage 26. An extensive network of 5-HT neurones appeared gradually, with a substantial subset crossing to the opposite side of the brain through the developing optic chiasma. 5,7-dihydroxytryptamine prevented the appearance of 5-HT. Depletion of 5-HT had little effect on development or swimming behaviour. Dopamine-containing neurones in the brain first differentiated at stage 35–36 and gradually increased in number up to stage 45–47, the latest stage examined. The functional role of 5-HT- or dopamine-containing neurones remains to be elucidated. We conclude that cell-type-specific antibodies can be used to identify neurones and glial cells at early times during neural development and may be useful tools in circumstances where functional identification is difficult.

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Cell Type-Specific Transcriptomics in the Brain

Journal of Neuroscience ◽

10.1523/jneurosci.0626-11.2011 ◽

2011 ◽

Vol 31 (19) ◽

pp. 6939-6943 ◽

Cited By ~ 76

Author(s):

B. W. Okaty ◽

K. Sugino ◽

S. B. Nelson

Keyword(s):

Cell Type ◽

Cell Type Specific ◽

The Brain

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Transposition-Driven Genomic Heterogeneity in the Drosophila Brain

Science ◽

10.1126/science.1231965 ◽

2013 ◽

Vol 340 (6128) ◽

pp. 91-95 ◽

Cited By ~ 137

Author(s):

Paola N. Perrat ◽

Shamik DasGupta ◽

Jie Wang ◽

William Theurkauf ◽

Zhiping Weng ◽

...

Keyword(s):

Expression Profiling ◽

Mushroom Body ◽

De Novo ◽

Brain Cell ◽

Specific Gene ◽

Cell Type ◽

Drosophila Brain ◽

Cell Type Specific ◽

Transposon Insertions ◽

The Brain

Recent studies in mammals have documented the neural expression and mobility of retrotransposons and have suggested that neural genomes are diverse mosaics. We found that transposition occurs among memory-relevant neurons in the Drosophila brain. Cell type–specific gene expression profiling revealed that transposon expression is more abundant in mushroom body (MB) αβ neurons than in neighboring MB neurons. The Piwi-interacting RNA (piRNA) proteins Aubergine and Argonaute 3, known to suppress transposons in the fly germline, are expressed in the brain and appear less abundant in αβ MB neurons. Loss of piRNA proteins correlates with elevated transposon expression in the brain. Paired-end deep sequencing identified more than 200 de novo transposon insertions in αβ neurons, including insertions into memory-relevant loci. Our observations indicate that genomic heterogeneity is a conserved feature of the brain.

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