Basal ganglia

Basal ganglia include a collection of subcortical nuclei, striatum and pallidum are subdivisions of the regions included in the collective name of basal ganglia. An important role of the basal ganglia is movement control and processing. Basal ganglia originates from the telencephalon (forebrain) and is developmentally related to the cerebral cortex, amygdala, olfactory and hippocampal formation. Caudate nucleus and putamen is often referred to as the striatum and is together with globus pallidus a central relay between the brainstem and cerebral cortex for signals of voluntary movements. The nucleus accumbens plays an important role in addiction and reward systems.

The transcriptome analysis shows that 85% (n=16752) of all human protein-coding genes (n=19670) are expressed in the human basal ganglia. Human one-to-one orthologues were investigated in pig and mouse brain, suggesting that 12008 of all mouse one-to-one orthologues (n=15160) are expressed in the mouse basal ganglia and that 12695 of all pig orthologues (n=14656) are expressed in the pig basal ganglia.

Gene classification based on regional RNA expression in human, pig and mouse basal ganglia defines 144 genes as basal ganglia enriched in either of the three species, and 35 out of those genes show highest expression levels in basal ganglia in all three species.

Figure 1. Schematic drawing of the human brain, indicating the location of basal ganglia from a sagittal view.

White and gray matter of the striatum

The unique look of the striatum is caused by bundles of white matter (myelinated axons densely packed in tracts) surrounded by gray matter, with more neuronal cell bodies. The type of neurons in the gray matter depend on what sub region of the basal ganglia. The visual effect of white vs gray matter in caudateputamen of the mouse brain is shown by TH - gray matter and CNP- white matter showing the opposite staining pattern.


TH

CNP

Regionally elevated expression in human basal ganglia



Figure 2. Schematic drawing of the human brain, indicating the location of basal ganglia from a coronal perspective.

The transcriptome analysis shows that 85% (n=16752) of all human proteins (n=19670) are expressed in basal ganglia. 260 genes show an elevated expression level in basal ganglia compared to other regions of the brain. The human basal ganglia sub regions include caudate nucleus, putamen and nucleus accumbens from both GTEx and FANTOM5 as well as globus pallidus data from FANTOM5. The highest mean value of the individual sub regions was used as representation of basal ganglia as one of the 10 brain regions.

  • 77 regionally enriched genes
  • 260 regionally elevated genes in total
  • 106 basal ganglia elevated genes are elevated in other tissues than brain

Table 1: Number of genes within the different categories of regionally elevated expression, in human basal ganglia

Specificity Number of Human elevated genes
Region enriched 77
Group enriched 121
Region enhanced 62
Elevated 260

Elevated expression in basal ganglia compared to other brain regions is divided into three different categories; regionally enriched (at least four-fold higher mRNA levels in basal ganglia compared to all other regions), group enriched (at least four-fold higher mRNA levels in a group of 2-5 regions) and regionally enhanced (at least four-fold higher mRNA levels in basal ganglia compared to the average of all regions), The number of genes in the individual category is shown in Table 1. In Table 2, the 12 genes with the highest level of regional specificity among the 77 enriched genes are listed.

Table 2. The 12 genes with the highest level of enriched expression in human basal ganglia. "Predicted localization" shows the classification of each gene into three main classes: Secreted, Membrane, and Intracellular, where the latter consists of genes without any predicted membrane and secreted features. RS-score (Regional Specificity score) corresponds to the score calculated as the fold change to the second highest tissue.

Gene Description Predicted location RS-score
HSD3B2 Hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2 Intracellular,Membrane 198
CYP17A1 Cytochrome P450 family 17 subfamily A member 1 Intracellular 103
RLN2 Relaxin 2 Intracellular,Secreted 64
HOXD12 Homeobox D12 Intracellular 41
SAG S-antigen visual arrestin Intracellular 39
CYP11A1 Cytochrome P450 family 11 subfamily A member 1 Intracellular 36
PTPRQ Protein tyrosine phosphatase, receptor type Q Intracellular,Membrane 24
ENTHD1 ENTH domain containing 1 Intracellular 20
MFSD2B Major facilitator superfamily domain containing 2B Membrane 16
KRTAP1-1 Keratin associated protein 1-1 Intracellular 14
TNFRSF8 TNF receptor superfamily member 8 Intracellular,Membrane 14
PENK Proenkephalin Secreted 12

Proteins specifically detected in human caudate nucleus

The tissue atlas includes TMA cores from caudate nucleus in standard profiling procedures, enabling high through put analysis of the protein location in caudate nucleus, here are a few examples of proteins specifically located in human caudate nucleus.


PENK

ADORA2A

CHAT

Regionally elevated expression in mouse basal ganglia

The mouse basal ganglia is similar to the human basal ganglia divided into striatum and pallidum, a collection of subcortical nuclei involved in movement control and processing. The sub regions of the mouse brain included in this analysis are caudateputamen, septum and ventral forebrain. The transcriptome analysis shows that 61% (n=12008) of all mouse one-to-one human orthologue genes (n=15160) are expressed in the basal ganglia and 244 genes show an elevated expression in basal ganglia compared to other regions of the brain.

Table 3: Number of genes within the different categories of regionally elevated expression, in mouse basal ganglia.

Specificity Number of Mouse elevated genes
Region enriched 50
Group enriched 144
Region enhanced 50
Elevated 244

Elevated expression in basal ganglia compared to other brain regions is divided into three different categories; regionally enriched (at least four-fold higher mRNA levels in basal ganglia compared to all other regions), group enriched (at least four-fold higher mRNA levels in a group of 2-5 regions) and regionally enhanced (at least four-fold higher mRNA levels in basal ganglia compared to the average of all regions), The number of genes in the individual category is shown in Table 3. In Table 4, the 12 genes with the highest level of regional specificity among the 50 enriched genes are listed.


Figure 2. Schematic drawing of the mouse brain, indicating the location of basal ganglia from a sagittal and coronal view.

Table 4: The 12 genes with the highest level of enriched expression in mouse cerebellum. "Predicted localization" shows the classification of each gene into three main classes: Secreted, Membrane, and Intracellular, where the latter consists of genes without any predicted membrane and secreted features. RS-score (Regional Specificity score) corresponds to the score calculated as the fold change to the second highest region.

Gene Description Predicted location RS-score
SERPINA9 Serpin family A member 9 Intracellular,Secreted 18
GPX6 Glutathione peroxidase 6 Secreted 16
CD4 CD4 molecule Intracellular,Membrane 15
SH3RF2 SH3 domain containing ring finger 2 Intracellular 14
IDO1 Indoleamine 2,3-dioxygenase 1 Intracellular 13
CLSPN Claspin Intracellular 12
GPR6 G protein-coupled receptor 6 Membrane 11
GPR88 G protein-coupled receptor 88 Membrane 11
PDE10A Phosphodiesterase 10A Intracellular 11
SCN4B Sodium voltage-gated channel beta subunit 4 Membrane 11
ADORA2A Adenosine A2a receptor Intracellular,Membrane 10
DRD2 Dopamine receptor D2 Intracellular,Membrane 10

Proteins specifically detected in mouse basal ganglia


CHAT

GNG7

RGS9

Regionally elevated expression in pig basal ganglia

The pig basal ganglia is similar to the human basal ganglia divided into striatum and pallidum, a collection of subcortical nuclei involved in movement control and processing. The sub regions included in this analysis are four different sub regional areas; caudate nucleus, putamen, septum and ventral pallidum. The transcriptome analysis shows that 65% (n=12695) of all pig genes (n=14656) are expressed in the cerebellum and 140 genes show an elevated expression in cerebellum compared to other regions of the brain.

Table 5: Number of genes within the different categories of regionally elevated expression, in pig basal ganglia

Specificity Number of Pig elevated genes
Region enriched 45
Group enriched 78
Region enhanced 17
Elevated 140


Figure 3. Schematic drawing of the pig brain, indicating the location of basal ganglia from a sagittal view. .

Elevated expression in basal ganglia compared to other brain regions is divided into three different categories; regionally enriched (at least four-fold higher mRNA levels in basal ganglia compared to all other regions), group enriched (at least four-fold higher mRNA levels in a group of 2-5 regions) and regionally enhanced (at least four-fold higher mRNA levels in basal ganglia compared to the average of all regions), The number of genes in the individual category is shown in Table 1. In Table 2, the 12 genes with the highest level of regional specificity among the 45 enriched genes are listed.

Table 6: The 12 genes with the highest level of enriched expression in pig basal ganglia. "Predicted localization" shows the classification of each gene into three main classes: Secreted, Membrane, and Intracellular, where the latter consists of genes without any predicted membrane and secreted features. RS-score (Regional Specificity score) corresponds to the score calculated as the fold change to the second highest region.

Gene Description Predicted location RS-score
ADORA2A Adenosine A2a receptor Intracellular,Membrane 95
GPR88 G protein-coupled receptor 88 Membrane 35
MBL2 Mannose binding lectin 2 Secreted 35
PRSS21 Serine protease 21 Intracellular 27
PPP1R1B Protein phosphatase 1 regulatory inhibitor subunit 1B Intracellular 21
FGF19 Fibroblast growth factor 19 Secreted 18
THEM5 Thioesterase superfamily member 5 Intracellular 15
CHRNE Cholinergic receptor nicotinic epsilon subunit Membrane 14
MUC6 Mucin 6, oligomeric mucus/gel-forming Intracellular,Secreted 14
DRD1 Dopamine receptor D1 Membrane 13
GNAL G protein subunit alpha L Intracellular 13
DRD3 Dopamine receptor D3 Membrane 12

Lateral ventricle wall

Caudate nucleus is a brain region close to the lateral ventricle, which means that although the ventricle wall is not part of the basal ganglia it is often included in the sampling of caudate nucleus, and we are able to see both RNA expression related to location specific cell types as well as proteins with a specific relation to the ependymal cells or subventricular zone.


CFAP53

MGARP

RSPH1

FOXJ1

SPAG6

ENO4

Extended human basal ganglia tissue section

A limited number of targets are selected for a more extensive profiling in human brain, providing a better overview of the regional location in the region of interest. Such is the case for SLC6A3, a protein specifically expressed in Substantia nigra but then transported into caudate nucleus and show variation within the caudate nucleus.


The standard setup in the Tissue Atlas, profiling human tissues, is based on Tissue Micro array technique, saving valuable tissue material as well as reagents but still provide a good tissue representation for protein profiling. However, due to the complex nature of the brain, with different cell types and subfields, sometimes a larger tissue samples is needed to fully understand the protein location. In table 7 the selected targets used for protein profiling on extended tissue material are listed.

Table 7. The following 35 genes have been analyzed using extended basal ganglia samples.

Gene Gene description Staining pattern
ADORA2A Adenosine A2a receptor Cytoplasmic positivity in subset of neurons. Synaptic and neuronal projection positivity.
ADRB3 Adrenoceptor beta 3 Strong neuronal projection positivity.
CACNG3 Calcium voltage-gated channel auxiliary subunit gamma 3 Synaptic staining.
CALY Calcyon neuron specific vesicular protein Strong cytoplasmic staining in neurons.
DCLK3 Doublecortin like kinase 3 Strong in astrocytes and projections.
DCX Doublecortin Cytoplasmic staining in neuronal cells.
DNER Delta/notch like EGF repeat containing Strong staining in a subset of neurons.
FGF11 Fibroblast growth factor 11 Cytoplasmic staining in neurons.
FGF2 Fibroblast growth factor 2 Nuclear staining in glia and neuropil positivity.
GNAL G protein subunit alpha L Synapse positivity.
GNG12 G protein subunit gamma 12 Axonal positivity.
GNG7 G protein subunit gamma 7 Axonal positivity.
GPRC5B G protein-coupled receptor class C group 5 member B Strong neuropil staining.
GRIK4 Glutamate ionotropic receptor kainate type subunit 4 Moderate staining in neuronal projections.
GRIN1 Glutamate ionotropic receptor NMDA type subunit 1 Moderate cytoplasmic staining in subset of neurons and weak synaptic staining.
HCN4 Hyperpolarization activated cyclic nucleotide gated potassium channel 4 Strong cytoplasmic positivity in neuronal cells and projections.
HTR6 5-hydroxytryptamine receptor 6 Cytoplasmic staining in neurons.
KCND2 Potassium voltage-gated channel subfamily D member 2 Membranous staining in subsets of neuronal cells.
KCNH8 Potassium voltage-gated channel subfamily H member 8 Staining in glial cells and projections.
KCNN3 Potassium calcium-activated channel subfamily N member 3 Glial staining.
KIAA1211L KIAA1211 like Stains neurons.
LAMP5 Lysosomal associated membrane protein family member 5 Synaptic and projection staining.
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