THAP1 modulates oligodendrocyte maturation by regulating ECM degradation in lysosomes
Mechanisms controlling myelination during central nervous system (CNS) maturation play a pivotal role in the development and refinement of CNS circuits. The transcription factor THAP1 is essential for timing the inception of myelination during CNS maturation through a cell-autonomous role in the oli...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2021-08, Vol.118 (31), p.1-11 |
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| creator | Yellajoshyula, Dhananjay Pappas, Samuel S. Rogers, Abigail E. Choudhury, Biswa Reed, Xylena Ding, Jinhui Cookson, Mark R. Shakkottai, Vikram G. Giger, Roman J. Dauer, William T. |
| description | Mechanisms controlling myelination during central nervous system (CNS) maturation play a pivotal role in the development and refinement of CNS circuits. The transcription factor THAP1 is essential for timing the inception of myelination during CNS maturation through a cell-autonomous role in the oligodendrocyte lineage. Here, we demonstrate that THAP1 modulates the extracellular matrix (ECM) composition by regulating glycosaminoglycan (GAG) catabolism within oligodendrocyte progenitor cells (OPCs). Thap1
−/− OPCs accumulate and secrete excess GAGs, inhibiting their maturation through an autoinhibitory mechanism. THAP1 controls GAG metabolism by binding to and regulating the GusB gene encoding β-glucuronidase, a GAG-catabolic lysosomal enzyme. Applying GAG-degrading enzymes or overexpressing β-glucuronidase rescues Thap1
−/− OL maturation deficits in vitro and in vivo. Our studies establish lysosomal GAG catabolism within OPCs as a critical mechanism regulating oligodendrocyte development. |
| doi_str_mv | 10.1073/pnas.2100862118 |
| format | Article |
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−/− OPCs accumulate and secrete excess GAGs, inhibiting their maturation through an autoinhibitory mechanism. THAP1 controls GAG metabolism by binding to and regulating the GusB gene encoding β-glucuronidase, a GAG-catabolic lysosomal enzyme. Applying GAG-degrading enzymes or overexpressing β-glucuronidase rescues Thap1
−/− OL maturation deficits in vitro and in vivo. Our studies establish lysosomal GAG catabolism within OPCs as a critical mechanism regulating oligodendrocyte development.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.2100862118</identifier><identifier>PMID: 34312226</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; Biological Sciences ; Catabolism ; Cells (biology) ; Central nervous system ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Extracellular matrix ; Extracellular Matrix - metabolism ; Gene Expression Regulation ; Glial stem cells ; Glycosaminoglycans ; In vivo methods and tests ; Lysosomes ; Lysosomes - metabolism ; Maturation ; Mice ; Mice, Knockout ; Myelination ; Progenitor cells</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2021-08, Vol.118 (31), p.1-11</ispartof><rights>Copyright National Academy of Sciences Aug 3, 2021</rights><rights>2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c443t-5379b702a9de3a08bf8aff288233314d2da80690979802e89034a555014ca83d3</citedby><cites>FETCH-LOGICAL-c443t-5379b702a9de3a08bf8aff288233314d2da80690979802e89034a555014ca83d3</cites><orcidid>0000-0002-6980-2058 ; 0000-0003-2742-6469 ; 0000-0003-1775-7504 ; 0000-0002-2031-0917 ; 0000-0002-1058-3831</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/27052725$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/27052725$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34312226$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yellajoshyula, Dhananjay</creatorcontrib><creatorcontrib>Pappas, Samuel S.</creatorcontrib><creatorcontrib>Rogers, Abigail E.</creatorcontrib><creatorcontrib>Choudhury, Biswa</creatorcontrib><creatorcontrib>Reed, Xylena</creatorcontrib><creatorcontrib>Ding, Jinhui</creatorcontrib><creatorcontrib>Cookson, Mark R.</creatorcontrib><creatorcontrib>Shakkottai, Vikram G.</creatorcontrib><creatorcontrib>Giger, Roman J.</creatorcontrib><creatorcontrib>Dauer, William T.</creatorcontrib><title>THAP1 modulates oligodendrocyte maturation by regulating ECM degradation in lysosomes</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Mechanisms controlling myelination during central nervous system (CNS) maturation play a pivotal role in the development and refinement of CNS circuits. The transcription factor THAP1 is essential for timing the inception of myelination during CNS maturation through a cell-autonomous role in the oligodendrocyte lineage. Here, we demonstrate that THAP1 modulates the extracellular matrix (ECM) composition by regulating glycosaminoglycan (GAG) catabolism within oligodendrocyte progenitor cells (OPCs). Thap1
−/− OPCs accumulate and secrete excess GAGs, inhibiting their maturation through an autoinhibitory mechanism. THAP1 controls GAG metabolism by binding to and regulating the GusB gene encoding β-glucuronidase, a GAG-catabolic lysosomal enzyme. Applying GAG-degrading enzymes or overexpressing β-glucuronidase rescues Thap1
−/− OL maturation deficits in vitro and in vivo. Our studies establish lysosomal GAG catabolism within OPCs as a critical mechanism regulating oligodendrocyte development.</description><subject>Animals</subject><subject>Biological Sciences</subject><subject>Catabolism</subject><subject>Cells (biology)</subject><subject>Central nervous system</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Extracellular matrix</subject><subject>Extracellular Matrix - metabolism</subject><subject>Gene Expression Regulation</subject><subject>Glial stem cells</subject><subject>Glycosaminoglycans</subject><subject>In vivo methods and tests</subject><subject>Lysosomes</subject><subject>Lysosomes - metabolism</subject><subject>Maturation</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Myelination</subject><subject>Progenitor cells</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkcFP2zAUh62JaRTYeadNkbjsEvr87MT2BQlVDJCYxqGcLTd2QqrE7uwEqf896Qpl28mH3_e-56cfIV8oXFAQbL7xJl0gBZAlUio_kBkFRfOSKzgiMwAUueTIj8lJSmsAUIWET-SYcUYRsZyRx-Xt1QPN-mDHzgwuZaFrm2CdtzFU28FlvRnGaIY2-Gy1zaJrdlzrm-x68TOzronG7tPWZ902hRR6l87Ix9p0yX1-fU_J44_r5eI2v_91c7e4us8rztmQF0yolQA0yjpmQK5qaeoapUTGGOUWrZFQKlBCSUAnFTBuiqIAyisjmWWn5HLv3Yyr3tnK-SGaTm9i25u41cG0-t_Et0-6Cc9aMl5KISbB91dBDL9Hlwbdt6lyXWe8C2PSOG0rOSoqJ_T8P3Qdxuin8yaqhMnG_wjne6qKIaXo6sNnKOhdZXpXmX6vbJr49vcNB_6town4ugfWaQjxkKOAAgUW7AWcqpvZ</recordid><startdate>20210803</startdate><enddate>20210803</enddate><creator>Yellajoshyula, Dhananjay</creator><creator>Pappas, Samuel S.</creator><creator>Rogers, Abigail E.</creator><creator>Choudhury, Biswa</creator><creator>Reed, Xylena</creator><creator>Ding, Jinhui</creator><creator>Cookson, Mark R.</creator><creator>Shakkottai, Vikram G.</creator><creator>Giger, Roman J.</creator><creator>Dauer, William T.</creator><general>National Academy of Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-6980-2058</orcidid><orcidid>https://orcid.org/0000-0003-2742-6469</orcidid><orcidid>https://orcid.org/0000-0003-1775-7504</orcidid><orcidid>https://orcid.org/0000-0002-2031-0917</orcidid><orcidid>https://orcid.org/0000-0002-1058-3831</orcidid></search><sort><creationdate>20210803</creationdate><title>THAP1 modulates oligodendrocyte maturation by regulating ECM degradation in lysosomes</title><author>Yellajoshyula, Dhananjay ; 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The transcription factor THAP1 is essential for timing the inception of myelination during CNS maturation through a cell-autonomous role in the oligodendrocyte lineage. Here, we demonstrate that THAP1 modulates the extracellular matrix (ECM) composition by regulating glycosaminoglycan (GAG) catabolism within oligodendrocyte progenitor cells (OPCs). Thap1
−/− OPCs accumulate and secrete excess GAGs, inhibiting their maturation through an autoinhibitory mechanism. THAP1 controls GAG metabolism by binding to and regulating the GusB gene encoding β-glucuronidase, a GAG-catabolic lysosomal enzyme. Applying GAG-degrading enzymes or overexpressing β-glucuronidase rescues Thap1
−/− OL maturation deficits in vitro and in vivo. Our studies establish lysosomal GAG catabolism within OPCs as a critical mechanism regulating oligodendrocyte development.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>34312226</pmid><doi>10.1073/pnas.2100862118</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-6980-2058</orcidid><orcidid>https://orcid.org/0000-0003-2742-6469</orcidid><orcidid>https://orcid.org/0000-0003-1775-7504</orcidid><orcidid>https://orcid.org/0000-0002-2031-0917</orcidid><orcidid>https://orcid.org/0000-0002-1058-3831</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Biological Sciences Catabolism Cells (biology) Central nervous system DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Extracellular matrix Extracellular Matrix - metabolism Gene Expression Regulation Glial stem cells Glycosaminoglycans In vivo methods and tests Lysosomes Lysosomes - metabolism Maturation Mice Mice, Knockout Myelination Progenitor cells |
| title | THAP1 modulates oligodendrocyte maturation by regulating ECM degradation in lysosomes |
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