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The mouse brain protein atlas



The first version of the mouse brain atlas launched as part of the Human Protein Atlas database in October 2015 covers 129 brain areas and subfields. The overview and preserved orientation has enabled us to annotate additional cell classes (ependymal), subpopulations (microglia, oligodendrocytes, and astrocytes), and subcellular locations (axon, dendrite, synapse, and glia endfeet). Integration of human and mouse brain data allows exploring translational aspects of brain proteomics, for example differences in expression and distribution of proteins, epitope homology, and antibody specificity and affinity in non-human samples of the mouse brain.

Figure 1. The different types of neurological cell classes (ependymal cells, purple), subpopulations (A=astrocytes, blue; M=microglia, brown; N=neuron, green; O=oligodendrocytes, orange), and subcellular locations (axon, dendrite, synapse, and glia endfeet).


GFAP - astrocyte
astrocyte

MBP - oligodendrocyte
oligodendrocyte

SLC2A1 - endothelia
endothelia

LIAS - ependymal cells
ependymal cells

RCN2 - neuronal soma
neuronal soma

ZNF3 - neuronal nucleus
neuronal nucleus

CAMK2B - neuronal dendrite
neuronal dendrite

SLC6A4 - neuronal axon
neuronal axon

SYNJ2BP - neuronal synapse
neuronal synapse


Table 1. The 88 genes included in the first version of the mouse brain protein atlas

Gene

Antibody

Cells and structures

AC007678.1 HPA002561 Soma, nucleus and dendrite in neurons.
Choroid plexus, ventricle wall and circumventricular organs of ependymal cells.
AMPD2 HPA045760 Soma and synapse in neurons.
Circumventricular organs of ependymal cells.
AP000275.65 HPA028849 Soma and dendrite in neurons.
AQP4 HPA014784 Endfeet in astrocytes.
ARFGEF1 HPA023822 Soma and dendrite in neurons.
Ventricle wall and circumventricular organs of ependymal cells.
ARHGAP1 HPA004689 Soma and synapse in neurons.
B3GNT6 HPA012158 Soma, dendrite and axon in neurons.
BCAR1 HPA042282 Dendrite in neurons.
BCL11B HPA049117 Nucleus in neurons.
BIRC3 HPA002317 Soma, nucleus and dendrite in neurons.
Choroid plexus, ventricle wall and circumventricular organs of ependymal cells.
C17orf75 HPA004061 Soma and dendrite in neurons.
C21orf59 HPA028849 Soma and dendrite in neurons.
CALB2 HPA007305 Soma, dendrite and axon in neurons.
CAMK2B HPA026307 Soma and dendrite in neurons.
DDX3X HPA001648 Soma in neurons.
DDX3Y HPA001648 Soma in neurons.
DDX3Y HPA001648 Soma in neurons.
DPP6 HPA050509 Soma and dendrite in neurons.
DTX4 HPA059294 Soma in neurons.
Choroid plexus of ependymal cells.
ECH1 HPA005835 Soma in astrocytes.
Soma and dendrite in neurons.
Endothelia.
Choroid plexus and circumventricular organs of ependymal cells.
EIF1AX HPA002561 Soma, nucleus and dendrite in neurons.
Choroid plexus, ventricle wall and circumventricular organs of ependymal cells.
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Mouse brain as a model for the human brain


Within mammalian evolution, the brain has undergone changes that resulted in increased capacities to process information and perform higher cognitive functions in primates and humans. These evolutionary processes mainly involve size expansion, not affecting the basic architecture of the brain and gene-expression in the various cell types that populate the brain. The driving force in evolution is genetic variability passed on from one generation to the other. Many of the mouse proteins have extensive homology with the human counterpart and this forms the basis of for using the mouse brain as a model for the corresponding human brain to explore the expression and distribution of proteins in the various regions and cells of the brain.



Regional organization of the brain


In the human protein atlas, three forebrain regions (cerebral cortex, hippocampus, and lateral ventricle) and one hindbrain (cerebellum) region is included. The much smaller mouse brain provides a more complete overview of many additional regions, such as thalamic, hypothalamic, and brainstem nuclei. This also enables annotation of cortical (layer 1-6) and hippocampal subfields (CA regions and dentate gyrus). Addition of brain regions with specialized functions increases the possibility of detecting protein expression and distribution of genes and proteins currently not detected in the human samples included in the human proteins atlas.


Figure 2. Example of a protein distribution in a single brain section of the mouse brain. A large 100 megapixel image with microscopic resolutions is generated. This image (a) reveals the regional protein distribution, in this case low density lipoprotein receptor-related protein associated protein 1 (LRPAP1). A more zoomed-in exploration of this image reveals protein levels in the 6 different cortical layers (b) with cellular resolution revealing information on the cellular and subcelluar distribution of proteins (c).



Specialized cells & functions


Neurons are the main signaling units in the central nervous system utilizing a number of released organic signaling molecules (glutamate, acetyl choline, GABA, or mono-amines) or peptides, and receptors and transporters in complex neuronal networks that process information and generate output. Glial cells, ependymal cells, and endothelial cells are specialized in supporting neurons and maintain homeostasis.

TH - neurotransmitter system
SST - neuropeptides

GABRA3 - receptors
AQP4 - homeostasis


Background


The tissue-micro array method used with the human protein atlas enabled the global mapping of proteins in the human body, including the brain. Currently, the human tissue atlas covers four areas of the human brain: cerebral cortex, hippocampus, lateral ventricle, and cerebellum. Due to the heterogeneous structure of the brain, with many nuclei and cell-types organized in complex networks, it is difficult to achieve a comprehensive overview in a 1 mm tissue sample. Analysis of more human brain samples, including smaller brain nuclei, is thus desirable in order to generate a more detailed map of protein distribution in the brain. Therefore, we here complemented the human brain atlas effort with a more comprehensive analysis of the mouse brain. Antibodies are selected based on certain criteria, and evaluated for specificity before analysis on mouse brain sections. A series of mouse brain sections is explored for protein expression and distribution in a large number of brain regions. The complete workflow in the mouse brain atlas is described in the slideshow.



This protein atlas of the mouse brain is a collaborative project between the human protein atlas project and department of neuroscience at the Karolinska Institute and is supported by SciLifeLab strategic (SFO) and national infrastructure funding.




UhlĂ©n et al (2015). Tissue-based map of the human proteome. Science
PubMed: 25613900 DOI: 10.1126/science.1260419

Yu et al (2015). Complementing tissue characterization by integrating transcriptome profiling from the Human Protein Atlas and from the FANTOM5 consortium. Nucleic Acids Res.
PubMed: 26117540 DOI: 10.1093/nar/gkv608

Fagerberg et al (2014). Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics.
PubMed: 24309898 DOI: 10.1074/mcp.M113.035600

Mulder et al (2007). Systematically generated antibodies against human gene products: high throughput screening on sections from the rat nervous system. Neuroscience.
PubMed: 17478047 DOI: 10.1016/j.neuroscience.2007.02.054

Mulder et al (2009). Tissue profiling of the mammalian central nervous system using human antibody-based proteomics. Mol Cell Proteomics.
PubMed: 19351664 DOI: 10.1074/mcp.M800539-MCP200

An anatomically comprehensive atlas of the adult human brain transcriptome

Allen brain atlas

Histology dictionary - the human brain

The mouse brain protein atlas
Mouse brain as a model for the human brain
Regional organization of the brain
Specialized cells & functions
Background
Relevant links and publications