Circadian Rhythms and Sleep Are Dependent Upon Expression Levels of Key Ubiquitin Ligase Ube3a
Normal neurodevelopment requires precise expression of the key ubiquitin ligase gene Ube3a. Comparing newly generated mouse models for Ube3a downregulation (models of Angelman syndrome) vs. Ube3a upregulation (models for autism), we find reciprocal effects of Ube3a gene dosage on phenotypes associat...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-03-01
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| Series: | Frontiers in Behavioral Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnbeh.2022.837523/full |
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| author | Shu-qun Shi Carrie E. Mahoney Pavel Houdek Wenling Zhao Matthew P. Anderson Matthew P. Anderson Xinming Zhuo Arthur Beaudet Alena Sumova Thomas E. Scammell Carl Hirschie Johnson |
| author_facet | Shu-qun Shi Carrie E. Mahoney Pavel Houdek Wenling Zhao Matthew P. Anderson Matthew P. Anderson Xinming Zhuo Arthur Beaudet Alena Sumova Thomas E. Scammell Carl Hirschie Johnson |
| author_sort | Shu-qun Shi |
| collection | DOAJ |
| description | Normal neurodevelopment requires precise expression of the key ubiquitin ligase gene Ube3a. Comparing newly generated mouse models for Ube3a downregulation (models of Angelman syndrome) vs. Ube3a upregulation (models for autism), we find reciprocal effects of Ube3a gene dosage on phenotypes associated with circadian rhythmicity, including the amount of locomotor activity. Consistent with results from neurons in general, we find that Ube3a is imprinted in neurons of the suprachiasmatic nuclei (SCN), the pacemaking circadian brain locus, despite other claims that SCN neurons were somehow exceptional to these imprinting rules. In addition, Ube3a-deficient mice lack the typical drop in wake late in the dark period and have blunted responses to sleep deprivation. Suppression of physical activity by light in Ube3a-deficient mice is not due to anxiety as measured by behavioral tests and stress hormones; quantification of stress hormones may provide a mechanistic link to sleep alteration and memory deficits caused by Ube3a deficiency, and serve as an easily measurable biomarker for evaluating potential therapeutic treatments for Angelman syndrome. We conclude that reduced Ube3a gene dosage affects not only neurodevelopment but also sleep patterns and circadian rhythms. |
| first_indexed | 2024-12-13T08:00:36Z |
| format | Article |
| id | doaj.art-b41a57afdeb4418496ca592e63b055fe |
| institution | Directory Open Access Journal |
| issn | 1662-5153 |
| language | English |
| last_indexed | 2024-12-13T08:00:36Z |
| publishDate | 2022-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Behavioral Neuroscience |
| spelling | doaj.art-b41a57afdeb4418496ca592e63b055fe2022-12-21T23:54:27ZengFrontiers Media S.A.Frontiers in Behavioral Neuroscience1662-51532022-03-011610.3389/fnbeh.2022.837523837523Circadian Rhythms and Sleep Are Dependent Upon Expression Levels of Key Ubiquitin Ligase Ube3aShu-qun Shi0Carrie E. Mahoney1Pavel Houdek2Wenling Zhao3Matthew P. Anderson4Matthew P. Anderson5Xinming Zhuo6Arthur Beaudet7Alena Sumova8Thomas E. Scammell9Carl Hirschie Johnson10Department of Biological Sciences, Vanderbilt University, Nashville, TN, United StatesDepartment of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, United StatesLaboratory of Biological Rhythms, Institute of Physiology of the Czech Academy of Sciences, Prague, CzechiaDepartment of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, United StatesDepartment of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, United StatesDepartment of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United StatesDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United StatesLuna Genetics, Inc., Houston, TX, United StatesLaboratory of Biological Rhythms, Institute of Physiology of the Czech Academy of Sciences, Prague, CzechiaDepartment of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, United StatesDepartment of Biological Sciences, Vanderbilt University, Nashville, TN, United StatesNormal neurodevelopment requires precise expression of the key ubiquitin ligase gene Ube3a. Comparing newly generated mouse models for Ube3a downregulation (models of Angelman syndrome) vs. Ube3a upregulation (models for autism), we find reciprocal effects of Ube3a gene dosage on phenotypes associated with circadian rhythmicity, including the amount of locomotor activity. Consistent with results from neurons in general, we find that Ube3a is imprinted in neurons of the suprachiasmatic nuclei (SCN), the pacemaking circadian brain locus, despite other claims that SCN neurons were somehow exceptional to these imprinting rules. In addition, Ube3a-deficient mice lack the typical drop in wake late in the dark period and have blunted responses to sleep deprivation. Suppression of physical activity by light in Ube3a-deficient mice is not due to anxiety as measured by behavioral tests and stress hormones; quantification of stress hormones may provide a mechanistic link to sleep alteration and memory deficits caused by Ube3a deficiency, and serve as an easily measurable biomarker for evaluating potential therapeutic treatments for Angelman syndrome. We conclude that reduced Ube3a gene dosage affects not only neurodevelopment but also sleep patterns and circadian rhythms.https://www.frontiersin.org/articles/10.3389/fnbeh.2022.837523/fullcircadiansleepubiquitin ligaseneurodevelopmental disordersAngelman syndromeUBE3A (E6AP) |
| spellingShingle | Shu-qun Shi Carrie E. Mahoney Pavel Houdek Wenling Zhao Matthew P. Anderson Matthew P. Anderson Xinming Zhuo Arthur Beaudet Alena Sumova Thomas E. Scammell Carl Hirschie Johnson Circadian Rhythms and Sleep Are Dependent Upon Expression Levels of Key Ubiquitin Ligase Ube3a Frontiers in Behavioral Neuroscience circadian sleep ubiquitin ligase neurodevelopmental disorders Angelman syndrome UBE3A (E6AP) |
| title | Circadian Rhythms and Sleep Are Dependent Upon Expression Levels of Key Ubiquitin Ligase Ube3a |
| title_full | Circadian Rhythms and Sleep Are Dependent Upon Expression Levels of Key Ubiquitin Ligase Ube3a |
| title_fullStr | Circadian Rhythms and Sleep Are Dependent Upon Expression Levels of Key Ubiquitin Ligase Ube3a |
| title_full_unstemmed | Circadian Rhythms and Sleep Are Dependent Upon Expression Levels of Key Ubiquitin Ligase Ube3a |
| title_short | Circadian Rhythms and Sleep Are Dependent Upon Expression Levels of Key Ubiquitin Ligase Ube3a |
| title_sort | circadian rhythms and sleep are dependent upon expression levels of key ubiquitin ligase ube3a |
| topic | circadian sleep ubiquitin ligase neurodevelopmental disorders Angelman syndrome UBE3A (E6AP) |
| url | https://www.frontiersin.org/articles/10.3389/fnbeh.2022.837523/full |
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