Abstract
Oligodendrocytes are the primary producers of many extracellular matrix (ECM)-related proteins found in the CNS. Therefore, oligodendrocytes play a critical role in the determination of brain stiffness, node of Ranvier formation, perinodal ECM deposition, and perineuronal net formation, all of which depend on the ECM. Nevertheless, the transcription factors that control ECM-related gene expression in oligodendrocytes remain unknown. Here, we found that the transcription factor Osterix (also known as Sp7) binds in proximity to genes important for CNS ECM and node of Ranvier formation and mediates their expression. Oligodendrocyte-specific ablation of Sp7 changes ECM composition and brain stiffness and results in aberrant node of Ranvier formation. Sp7 is known to control osteoblast maturation and bone formation. Our comparative analyses suggest that Sp7 plays a conserved biological role in oligodendrocytes and in bone-forming cells, where it mediates brain and bone tissue stiffness by controlling expression of ECM components.
Original language | English (US) |
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Pages (from-to) | 247-263.e6 |
Journal | Neuron |
Volume | 112 |
Issue number | 2 |
DOIs | |
State | Published - Jan 17 2024 |
Funding
This research was supported by an R01NS067550 grant to B.E. and B.P. In addition, B.P. is supported by NIH R01NS109372 , R01NS099334 , and 1RF1AG072080 grants and by the National Multiple Sclerosis Society ( RG-1807-32005 ) grant. B.P. is also supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the Rampy MS Research Foundation (B.P.). B.E. is also supported by the DOD W81XWH2210386 grant. M.P. is supported by NIH R35NS132349 . A.D. is recipient of the British Council GROWTH fellowship and the Dr. Willem Been Legacy award. A.E. is supported by ICRF grant 01301 . Some of the imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. The authors would like to thank Dr. Gajendra Shekhawa from the Atomic and Nanoscale Characterization Center at Northwestern University for his skillful help with ATM analysis. The authors would like to thank Professor Hironori Hojo from the University of Tokyo for kindly sharing his detailed Sp7-Chip-seq protocol and the late Professor Benoit de Crombrugghe from MD Anderson Cancer Center for providing the Sp7 floxed mice. Behavioral assays were performed at the Northwestern University Behavioral Phenotyping Core Facility. This research was supported by an R01NS067550 grant to B.E. and B.P. In addition, B.P. is supported by NIH R01NS109372, R01NS099334, and 1RF1AG072080 grants and by the National Multiple Sclerosis Society (RG-1807-32005) grant. B.P. is also supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the Rampy MS Research Foundation (B.P.). B.E. is also supported by the DOD W81XWH2210386 grant. M.P. is supported by NIH R35NS132349. A.D. is recipient of the British Council GROWTH fellowship and the Dr. Willem Been Legacy award. A.E. is supported by ICRF grant 01301. Some of the imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. B.E. and B.P. designed the study. B.E. injected the animals, harvested the tissues, cultured the primary oligodendrocytes, and performed the ATAC-seq experiment, the bulk RNA-seq experiment, and TEM analysis. M.A. and H.A. performed the IHC experiments and analyzed data. M.P. and K.R. isolated and cultured the primary hippocampal neurons. Y.D. performed the RNA-scope experiment. A.D. and S.I. performed the ChIP-seq experiments and analyzed the RNA-seq, ATAC-seq, and the ChiP-seq experiments. A.E. designed and analyzed the RNA-seq, ATAC-seq, and the ChiP-seq experiments. B.E. and B.P. wrote the manuscript with inputs from all authors. The authors declare no competing interests.
Keywords
- Sp7
- extracellular matrix
- myelin
- myelination
- node of Ranvier
- oligodendrocyte
- osterix
- remyelination
- transcription factor
ASJC Scopus subject areas
- General Neuroscience