The Ormdl genes regulate the sphingolipid synthesis pathway to ensure proper myelination and neurologic function in mice
Sphingolipids are membrane and bioactive lipids that are required for many aspects of normal mammalian development and physiology. However, the importance of the regulatory mechanisms that control sphingolipid levels in these processes is not well understood. The mammalian ORMDL proteins (ORMDL1, 2 and 3) mediate feedback inhibition of the de novo synthesis pathway of sphingolipids by inhibiting serine palmitoyl transferase in response to elevated ceramide levels. To understand the function of ORMDL proteins in vivo, we studied mouse knockouts (KOs) of the Ormdl genes. We found that Ormdl1 and Ormdl3 function redundantly to suppress the levels of bioactive sphingolipid metabolites during myelination of the sciatic nerve. Without proper ORMDL-mediated regulation of sphingolipid synthesis, severe dysmyelination results. Our data indicate that the Ormdls function to restrain sphingolipid metabolism in order to limit levels of dangerous metabolic intermediates that can interfere with essential physiological processes such as myelination.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:8 |
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| Enthalten in: |
eLife - 8(2019) vom: 27. Dez. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Clarke, Benjamin A [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 12.06.2020 Date Revised 12.06.2020 published: Electronic Citation Status MEDLINE |
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| doi: |
10.7554/eLife.51067 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM304805904 |
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| 100 | 1 | |a Clarke, Benjamin A |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The Ormdl genes regulate the sphingolipid synthesis pathway to ensure proper myelination and neurologic function in mice |
| 264 | 1 | |c 2019 | |
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| 500 | |a Date Completed 12.06.2020 | ||
| 500 | |a Date Revised 12.06.2020 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Sphingolipids are membrane and bioactive lipids that are required for many aspects of normal mammalian development and physiology. However, the importance of the regulatory mechanisms that control sphingolipid levels in these processes is not well understood. The mammalian ORMDL proteins (ORMDL1, 2 and 3) mediate feedback inhibition of the de novo synthesis pathway of sphingolipids by inhibiting serine palmitoyl transferase in response to elevated ceramide levels. To understand the function of ORMDL proteins in vivo, we studied mouse knockouts (KOs) of the Ormdl genes. We found that Ormdl1 and Ormdl3 function redundantly to suppress the levels of bioactive sphingolipid metabolites during myelination of the sciatic nerve. Without proper ORMDL-mediated regulation of sphingolipid synthesis, severe dysmyelination results. Our data indicate that the Ormdls function to restrain sphingolipid metabolism in order to limit levels of dangerous metabolic intermediates that can interfere with essential physiological processes such as myelination | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a biochemistry | |
| 650 | 4 | |a cell biology | |
| 650 | 4 | |a chemical biology | |
| 650 | 4 | |a metabolism | |
| 650 | 4 | |a mouse | |
| 650 | 4 | |a mouse models | |
| 650 | 4 | |a myelination | |
| 650 | 4 | |a sphingolipids | |
| 650 | 7 | |a Ceramides |2 NLM | |
| 650 | 7 | |a Membrane Proteins |2 NLM | |
| 650 | 7 | |a ORMDL1 protein, mouse |2 NLM | |
| 650 | 7 | |a ORMDL2 protein, human |2 NLM | |
| 650 | 7 | |a ORMDL3 protein, mouse |2 NLM | |
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| 700 | 1 | |a Blain, Hailey |e verfasserin |4 aut | |
| 700 | 1 | |a Schwartz, Ronit |e verfasserin |4 aut | |
| 700 | 1 | |a Huso, Vienna L |e verfasserin |4 aut | |
| 700 | 1 | |a Byrnes, Colleen |e verfasserin |4 aut | |
| 700 | 1 | |a Tuymetova, Galina |e verfasserin |4 aut | |
| 700 | 1 | |a Dunn, Teresa M |e verfasserin |4 aut | |
| 700 | 1 | |a Allende, Maria L |e verfasserin |4 aut | |
| 700 | 1 | |a Proia, Richard L |e verfasserin |4 aut | |
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