THE HUMAN TISSUE PROTEOMES

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 157 genes included in the first version of the mouse brain protein atlas

Gene

Antibody

Cells and structures

ACADL HPA011990 Soma and synapse in neurons.
ADCYAP1 HPA065887 Axon and synapse in neurons.
ALDH1A1 HPA002123 Endfeet in astrocytes.
ALDOC HPA067442 Soma in astrocytes.
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.
BBOX1 HPA027823 Soma in neurons.
BCAP31 HPA003906 Synapse in neurons.
BCAR1 HPA042282 Soma and dendrite in neurons.
BCL11B HPA049117 Nucleus in neurons.
BCL2L2-PABPN1 HPA000637 Soma and synapse in neurons.
BIRC3 HPA002317 Soma, nucleus and dendrite in neurons.
Choroid plexus, ventricle wall and circumventricular organs of ependymal cells.
BMPER HPA018083 Soma, nucleus and synapse in neurons.
C12orf10 HPA038626 Soma and endfeet in astrocytes.
C17orf67 HPA043479 Dendrite and synapse in neurons.
C17orf75 HPA004061 Soma and dendrite in neurons.
C21orf59 HPA028849 Soma and dendrite in neurons.
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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 caudate) 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, caudate 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 against proteins relevant for brain (non-housekeeping) are selected based on homology, 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.




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