Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Sep 27;22(19):10387.
doi: 10.3390/ijms221910387.

Dynamic Changes of Brain Cilia Transcriptomes across the Human Lifespan

Siwei Chen  1   2 , Wedad Alhassen  3 , Roudabeh Vakil Monfared  3 , Benjamin Vachirakorntong  3 , Surya M Nauli  4 , Pierre Baldi  1   2 , Amal Alachkar  2   3
Affiliations

Dynamic Changes of Brain Cilia Transcriptomes across the Human Lifespan

Siwei Chen et al. Int J Mol Sci. .

Abstract

Almost all brain cells contain primary cilia, antennae-like microtubule sensory organelles, on their surface, which play critical roles in brain functions. During neurodevelopmental stages, cilia are essential for brain formation and maturation. In the adult brain, cilia play vital roles as signaling hubs that receive and transduce various signals and regulate cell-to-cell communications. These distinct roles suggest that cilia functions, and probably structures, change throughout the human lifespan. To further understand the age-dependent changes in cilia roles, we identified and analyzed age-dependent patterns of expression of cilia's structural and functional components across the human lifespan. We acquired cilia transcriptomic data for 16 brain regions from the BrainSpan Atlas and analyzed the age-dependent expression patterns using a linear regression model by calculating the regression coefficient. We found that 67% of cilia transcripts were differentially expressed genes with age (DEGAs) in at least one brain region. The age-dependent expression was region-specific, with the highest and lowest numbers of DEGAs expressed in the ventrolateral prefrontal cortex and hippocampus, respectively. The majority of cilia DEGAs displayed upregulation with age in most of the brain regions. The transcripts encoding cilia basal body components formed the majority of cilia DEGAs, and adjacent cerebral cortices exhibited large overlapping pairs of cilia DEGAs. Most remarkably, specific α/β-tubulin subunits (TUBA1A, TUBB2A, and TUBB2B) and SNAP-25 exhibited the highest rates of downregulation and upregulation, respectively, across age in almost all brain regions. α/β-tubulins and SNAP-25 expressions are known to be dysregulated in age-related neurodevelopmental and neurodegenerative disorders. Our results support a role for the high dynamics of cilia structural and functional components across the lifespan in the normal physiology of brain circuits. Furthermore, they suggest a crucial role for cilia signaling in the pathophysiological mechanisms of age-related psychiatric/neurological disorders.

Keywords: brain; cilia; human; lifespan; linear regression; transcriptome.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interest.

Figures

Figure 1
Figure 1
Age-dependent gene expressions of cilia genes abundance in the human brain. (a) Representative brain section from human brains (BrainMaps: An Interactive Multiresolution Brain Atlas; http://brainmaps.org [retrieved on 2 August 2021] [26] showing the regions and nuclei from which tissues were collected: anterior (rostral) cingulate (medial prefrontal) cortex (ACC), amygdaloid (Amy), Cerebellar cortex (Cer), dorsolateral prefrontal cortex (DLPC), Hippocampus (Hipp), Inferolateral temporal cortex (area TEv, area 20) (ITC), Mediodorsal nucleus of the thalamus (MTh), Orbital frontal cortex (OFC), posterior (caudal) superior temporal cortex (area 22c) (PSTC), posteroventral (inferior) parietal cortex (PPC), primary auditory cortex (core) (PAC), primary motor cortex (area M1, area 4) (PMC), primary visual cortex (striate cortex, area V117) (PVC), primary somatosensory cortex (area S1, areas 3,1,2) (PSSC), Striatum (Str), and ventrolateral prefrontal cortex (VLPC).(b) Stacked bar chart shows the total number of cilia genes that are differentially expressed with age (cilia DEGAs) in the whole brain and each of the 16 brain regions, with the exact number of cilia DEGAs that are upregulated and downregulated. The numbers on the top of bars represent the number of DEGAs in brain regions.
Figure 2
Figure 2
Linear regression model fitting the effect of age on cilia gene expression in 16 human brain regions. (a–p): scatter plots of gene expression patterns of cilia genes that are differentially expressed with age (cilia DEGAs) in each of the 16 human brain regions. (Left panels): Age-dependent upregulated cilia DEGAs in brain regions. (Middle panels): Age-dependent downregulated cilia DEGAs in brain regions. (Right panels): Volcano plot of regression coefficients and p-values in brain regions. The x-axis is the age effect on cilia gene expression of cilia DEGAs measured by regression coefficient. The y-axis represents the −log10 (p-value). The larger −log10 (p-value) value, the more significance. The orange dots represent age-dependent upregulated cilia DEGAs and the blue dots represent age-dependent downregulated cilia DEGAs.
Figure 2
Figure 2
Linear regression model fitting the effect of age on cilia gene expression in 16 human brain regions. (a–p): scatter plots of gene expression patterns of cilia genes that are differentially expressed with age (cilia DEGAs) in each of the 16 human brain regions. (Left panels): Age-dependent upregulated cilia DEGAs in brain regions. (Middle panels): Age-dependent downregulated cilia DEGAs in brain regions. (Right panels): Volcano plot of regression coefficients and p-values in brain regions. The x-axis is the age effect on cilia gene expression of cilia DEGAs measured by regression coefficient. The y-axis represents the −log10 (p-value). The larger −log10 (p-value) value, the more significance. The orange dots represent age-dependent upregulated cilia DEGAs and the blue dots represent age-dependent downregulated cilia DEGAs.
Figure 2
Figure 2
Linear regression model fitting the effect of age on cilia gene expression in 16 human brain regions. (a–p): scatter plots of gene expression patterns of cilia genes that are differentially expressed with age (cilia DEGAs) in each of the 16 human brain regions. (Left panels): Age-dependent upregulated cilia DEGAs in brain regions. (Middle panels): Age-dependent downregulated cilia DEGAs in brain regions. (Right panels): Volcano plot of regression coefficients and p-values in brain regions. The x-axis is the age effect on cilia gene expression of cilia DEGAs measured by regression coefficient. The y-axis represents the −log10 (p-value). The larger −log10 (p-value) value, the more significance. The orange dots represent age-dependent upregulated cilia DEGAs and the blue dots represent age-dependent downregulated cilia DEGAs.
Figure 2
Figure 2
Linear regression model fitting the effect of age on cilia gene expression in 16 human brain regions. (a–p): scatter plots of gene expression patterns of cilia genes that are differentially expressed with age (cilia DEGAs) in each of the 16 human brain regions. (Left panels): Age-dependent upregulated cilia DEGAs in brain regions. (Middle panels): Age-dependent downregulated cilia DEGAs in brain regions. (Right panels): Volcano plot of regression coefficients and p-values in brain regions. The x-axis is the age effect on cilia gene expression of cilia DEGAs measured by regression coefficient. The y-axis represents the −log10 (p-value). The larger −log10 (p-value) value, the more significance. The orange dots represent age-dependent upregulated cilia DEGAs and the blue dots represent age-dependent downregulated cilia DEGAs.
Figure 3
Figure 3
Overlap of cilia DEGAs transcriptome in brain nuclei/regions. (a) Heatmap of region-by-region intersections of the cilia DEGAs genes. The size of the intersections ranged from 9 (light blue) to 93 transcripts (dark blue), which occurred in two intersections. (b) Network graph represents the cilia DEGAs-region interaction, using “spring” layout from the NetworkX package with Python. Each blue node presents one of the cilia DEGAs, and each red node presents the brain. Edges were drawn to connect cilia DEGAs nodes to brain regions nodes where they are expressed. The node’s size is proportional to its connectedness in the graph: the more connected the node is, the bigger its size.
Figure 4
Figure 4
Sub-structural organization of cilia DEGAs genes. (a) Percentages of the total DEGAs genes in each of the cilia sub-structural compartments as proportions to the total cilia genes in each sub-structural compartments. (b) Heatmap of cilia sub-structural DEGAs presented as proportions to the total cilia transcripts in 16 brain regions. Yellow indicates a high percentage of DEGAs genes, and dark blue indicates no DEGAs genes in a given brain region. (c) Heatmap of the cilia sub-structural DEGAs presented as proportions to the total corresponding sub-structural transcripts in 16 brain regions. Dark blue indicates a high percentage of upregulated genes, and white indicates no DEGAs in a given brain region.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Liu Z., Tu H., Kang Y., Xue Y., Ma D., Zhao C., Li H., Wang L., Liu F. Primary cilia regulate hematopoietic stem and progenitor cell specification through Notch signaling in zebrafish. Nat. Commun. 2019;10:1839. doi: 10.1038/s41467-019-09403-7. - DOI - PMC - PubMed
    1. Guo J., Otis J.M., Higginbotham H., Monckton C., Cheng J., Asokan A., Mykytyn K., Caspary T., Stuber G.D., Anton E.S. Primary Cilia Signaling Shapes the Development of Interneuronal Connectivity. Dev. Cell. 2017;42:286–300.e4. doi: 10.1016/j.devcel.2017.07.010. - DOI - PMC - PubMed
    1. Nechipurenko I.V., Doroquez D.B., Sengupta P. Primary cilia and dendritic spines: Different but similar signaling compart-ments. Mol. Cells. 2013;36:288–303. doi: 10.1007/s10059-013-0246-z. - DOI - PMC - PubMed
    1. Breunig J.J., Sarkisian M.R., Arellano J.I., Morozov Y.M., Ayoub A.E., Sojitra S., Wang B., Flavell R.A., Rakic P., Town T. Primary cilia regulate hippocampal neurogenesis by mediating sonic hedgehog signaling. Proc. Natl. Acad. Sci. USA. 2008;105:13127–13132. doi: 10.1073/pnas.0804558105. - DOI - PMC - PubMed
    1. Han Y.G., Spassky N., Romaguera-Ros M., Garcia-Verdugo J.M., Aguilar A., Schneider-Maunoury S., Alvarez-Buylla A. Hedgehog signaling and primary cilia are required for the formation of adult neural stem cells. Nat. Neurosci. 2008;11:277–284. doi: 10.1038/nn2059. - DOI - PubMed

Substances