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Adult Mouse Leptomeninges Exhibit Regional and Age-related Cellular Heterogeneity Implicating Mental Disorders

ABSTRACT: Transplantation of retinal pigment epithelial (RPE) cells holds great promise for RPE tissue repair in patients with retinal degenerative diseases, such as age-related macular The leptomeninges envelop the central nervous system (CNS) and contribute to cerebrospinal fluid (CSF) production and homeostasis. We analyzed the meninges overlying the anterior or posterior forebrain in the adult mouse by single nuclear RNA-sequencing (snucRNA-seq). This revealed regional differences in fibroblast and endothelial cell composition and gene expression. Surprisingly, these non-neuronal cells co-expressed genes implicated in neural functions. The regional differences changed with aging, from 3 to 18 months. Cytokine analysis revealed specific soluble factor production from anterior vs posterior meninges that also altered with age. Secreted factors from the leptomeninges from different regions and ages differentially impacted the survival of anterior or posterior cortical neuronal subsets, neuron morphology, and glia proliferation. These findings suggest that meningeal dysfunction in different brain regions could contribute to specific neural pathologies. The disease-associations of meningeal cell genes differentially expressed with region and age were significantly enriched for mental and substance abuse disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE242810 | GEO | 2023/09/10

REPOSITORIES: GEO

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Project description:Proper spatial differentiation of retinal cell types is necessary for normal human vision. Many retinal diseases, such as Best disease and male germ cell associated kinase (MAK)-associated retinitis pigmentosa, preferentially affect distinct topographic regions of the retina. While much is known about the distribution of cell types in the retina, the distribution of molecular components across the posterior pole of the eye has not been well-studied. To investigate regional difference in molecular composition of ocular tissues, we assessed differential gene expression across the temporal, macular, and nasal retina and retinal pigment epithelium (RPE)/choroid of human eyes using RNA-Seq. RNA from temporal, macular, and nasal retina and RPE/choroid from four human donor eyes was extracted, poly-A selected, fragmented, and sequenced as 100 bp read pairs. Digital read files were mapped to the human genome and analyzed for differential expression using the Tuxedo software suite. Retina and RPE/choroid samples were clearly distinguishable at the transcriptome level. Numerous transcription factors were differentially expressed between regions of the retina and RPE/choroid. Photoreceptor-specific genes were enriched in the peripheral samples, while ganglion cell and amacrine cell genes were enriched in the macula. Within the RPE/choroid, RPE-specific genes were upregulated at the periphery while endothelium associated genes were upregulated in the macula. Consistent with previous studies, BEST1 expression was lower in macular than extramacular regions. The MAK gene was expressed at lower levels in macula than in extramacular regions, but did not exhibit a significant difference between nasal and temporal retina. The regional molecular distinction is greatest between macula and periphery and decreases between different peripheral regions within a tissue. Datasets such as these can be used to prioritize candidate genes for possible involvement in retinal diseases with regional phenotypes. Reprinted from <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=25446321">Whitmore, S.S., Wagner, A.H., DeLuca, A.P., Drack, A.V., Stone, E.M., Tucker, B.A., Zeng, S., Braun, T.A., Mullins, R.F., Scheetz, T.E., 2014. Transcriptomic analysis across nasal, temporal, and macular regions of human neural retina and RPE/choroid by RNA-Seq. Experimental Eye Research</a>. Used under <a href="http://creativecommons.org/licenses/by-nc-sa/3.0/">Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported </a>license. Additional RNA sequencing was performed on temporal, macular, nasal, inferior, and superior retina from a fifth subject and is included in this dataset. See original publication for details.

Project description:AbstractBlindness or vision loss due to neuroretinal and photoreceptor degeneration affects millions of individuals worldwide. In numerous neurodegenerative diseases, including age related macular degeneration, dysregulated immune response mediated retinal degeneration have been found to play a critical role in the disease pathogenesis. To better understand the pathogenic mechanisms underlying the retinal degeneration, we used a mouse model of systemic immune activation where we infected mice with lymphocytic choriomeningitis virus (LCMV) clone 13. Here we evaluated the effects of LCMV infection and present a comprehensive discovery-based proteomic investigation using tandem mass tag (TMT) labelling and high-resolution liquid chromatography - tandem mass spectrometry (LC-MS/MS). Changes in protein regulation in the posterior part of the eye, neuroretina and RPE/choroid, were compared to spleen as a secondary lymphoid organ and to the kidney as a non-lymphoid but encapsulated organ at 1, 8 and 28 weeks of infection. Using bioinformatic tools, we found several proteins responsible for maintaining normal tissue homeostasis to be differentially regulated in the neuroretina and the RPE/choroid during the degenerative process. Additionally, in the organs we observed several important protein pathways contributing to cellular homeostasis and tissue development to be perturbed and associated with LCMV mediated inflammation promoting disease progression. Our findings suggest that the response to a systemic chronic infection differs between neuroretina, and the RPE/choroid and the processes induced by chronic systemic infection in RPE/choroid are not unlike those induced in non-immune privileged organs such as the kidney and spleen. Overall, our data provides detailed insight into several molecular mechanisms of retinal degeneration and highlights various novel proteins pathways which further suggest that the posterior part of the eye is not an isolated immunological entity despite of the existence of neuroretinal immune privilege.

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Adult Mouse Leptomeninges Exhibit Regional and Age-related Cellular Heterogeneity Implicating Mental Disorders

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