The mouse brain protein atlas

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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).

Table 1. The 259 genes included in the first version of the mouse brain protein atlas

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.

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.

Relevant links and publications

Uhlén M et al, 2015. Tissue-based map of the human proteome. Science
PubMed: 25613900 DOI: 10.1126/science.1260419

Yu NY 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 L 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 J 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 J 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

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