Gene expression atlas of the mouse central nervous system: impact and interactions of age, energy intake and gender

Abstract

Background: The structural and functional complexity of the mammalian central nervous system (CNS) is organized and modified by complicated molecular signaling processes that are poorly understood.

Results: We measured transcripts of 16,896 genes in 5 CNS regions from cohorts of young, middle-aged and old male and female mice that had been maintained on either a control diet or a low energy diet known to retard aging. Each CNS region (cerebral cortex, hippocampus, striatum, cerebellum and spinal cord) possessed its own unique transcriptome fingerprint that was independent of age, gender and energy intake. Less than 10% of genes were significantly affected by age, diet or gender, with most of these changes occurring between middle and old age. The transcriptome of the spinal cord was the most responsive to age, diet and gender, while the striatal transcriptome was the least responsive. Gender and energy restriction had particularly robust influences on the hippocampal transcriptome of middle-aged mice. Prominent functional groups of age- and energy-sensitive genes were those encoding proteins involved in DNA damage responses (Werner and telomere-associated proteins), mitochondrial and proteasome functions, cell fate determination (Wnt and Notch signaling) and synaptic vesicle trafficking.

Conclusion: Mouse CNS transcriptomes responded to age, energy intake and gender in a regionally distinctive manner. The systematic transcriptome dataset also provides a window into mechanisms of age-, diet- and sex-related CNS plasticity and vulnerability.

Figure 1

CNS region-specific gene expression patterns. (a) PCA of transcriptomes of the indicated CNS regions inclusive of all ages, diets and genders. The results show that each region of CNS has its own molecular signature that is independent of age, diet and gender. (b) PCA of transcriptomes of the CNS regions and non-CNS region (lung) inclusive of all ages, diets and genders.

Figure 2

CNS age-related gene expression patterns. (a) For any given gene there are six possible patterns of gene expression from young to middle-aged to old. For approximately 95% of the genes, there was no significant change (p < 0.05 and Z-ratio ≥ 1.50 or ≤ -1.50) in expression across ages (pattern 1). For most CNS regions, pattern 2 (change from middle-aged to old) was the most common. Red, upregulated; blue, downregulated. (b) Comparison of the numbers of genes that were significantly affected by age in each CNS region. The transcriptomes of the cortex, hippocampus and spinal cord were the most responsive to age, while the transcriptome of the striatum was stable over time. The spinal cord transcriptome was remarkable for the large number of genes significantly upregulated with advancing age, in contrast to other CNS regions in which most genes were downregulated with advancing age. Gene lists are in Table S2a,b in Additional data file 1.

Figure 3

Functional categorization of CNS age-related genes. Numbers above bars are the actual numbers of genes affected by aging in that gene category/CNS region. Functional categories (FC): FC1, DNA damage and repair; FC2, transcription regulators; FC3, RNA editing/processing; FC4, protein synthesis/degradation; FC5, signal transduction; FC6, growth factors and signaling; FC7, channels and transporters; FC8, cytoskeleton; FC9, trafficking; FC10, other synaptic function related ; FC11, stress response; FC12, immune responsive; FC13, mitochondrial function; FC14, cell cycle; FC15, glucose metabolism; FC16, lipid metabolism; FC17, amino acid metabolism. Gene lists are in Table S3 in Additional data file 1.

Figure 4

CNS transcriptomes respond to caloric restriction in a region- and age-dependent manner. (a) CNS gene expression responses to CR. (b) Metabolic and signaling pathways in which genes were significantly affected by CR in all five CNS regions. Red, upregulated; blue, downregulated. (c) CNS AAGs reverted by CR. The percentage of AAGs reverted by CR is shown at the top of each bar. Note that the spinal cord exhibits a much larger percentage of upregulated AAGs that are reverted by CR compared to the other CNS regions. Gene lists are in Table S4a,c in Additional data file 1.

Figure 5

Gender-specific modulation of CNS transcriptomes by age and diet. (a) Numbers of genes that are differentially expressed in males and females in an age-dependent manner. (b) Genes differentially affected by CR in males and females. (c) Gene cluster analysis comparison of the effects of CR on hippocampal transcriptomes of male and female mice of different ages. Note the similarities in responses of young and middle-aged male and female mice, and the striking differential response of males and females to CR in old mice. (d) Age-responsive genes that were reverted by CR in males compared to females. Gene lists are in Tables S5a-d in Additional data file 1.

Figure 6

Pathway transcriptomes responsive to age, diet and gender. (a) Left: the ubiquitin-proteasome protein degradation pathway. E1, E2 and E3 are ubiquitin activating, conjugating and ligating enzymes, respectively. Ub, ubiquitin; 19S and 20S are proteasome subunits. Middle: the Wnt β-catenin signaling pathways. Fzd, frizzled; LRP, lipoprotein-related protein; DKK1, dickkopf 1; Frat, frequently rearranged in advanced T-cell lymphomas-1; GSK3β, glycogen synthase kinase-3β; Nlk, nemo-like kinase; NF-AT, nuclear factor of activated T cells; TCF, T cell-specific transcription factor; Tab1, TGF-beta activated kinase-1 binding protein-1; Tak1, TGF-beta-activated kinase 1. Right: Werner (WRN) interacting proteins involved in DNA repair and telomere homeostasis. PARP-1, poly (ADP-ribose) polymerase 1; FEN-1, flap endonuclease 1; DNAPKcs, DNA-dependent protein kinase catalytic subunit; Ku, Ku p70/p80 antigen; MRN, MRE11-RAD50-NBS1 protein complex; BLM, Bloom syndrome; TRF1 and TRF2, telomere repeat-binding factors 1 and 2. (b) Frequency of UPS pathway gene sensitivity to age, gender and diet in the striatum (genes identified based on a threshold of perturbation probability ≥ 0.10). (c) The perturbation probability of Uchl1 gene and/or its combinations in different CNS regions during aging and in response to CR.