Targeting of retrovirus-derived Rtl8a/8b causes late-onset obesity, reduced social response and increased apathy-like behaviour
Retrotransposon Gag-like (RTL) 8A, 8B and 8C are eutherian-specific genes derived from a certain retrovirus. They cluster as a triplet of genes on the X chromosome, but their function remains unknown. Here, we demonstrate that Rtl8a and Rtl8b play important roles in the brain: their double knockout...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
The Royal Society
2025-01-01
|
| Series: | Open Biology |
| Subjects: | |
| Online Access: | https://royalsocietypublishing.org/doi/10.1098/rsob.240279 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832583152095199232 |
|---|---|
| author | Yoshifumi Fujioka Hirosuke Shiura Masayuki Ishii Ryuichi Ono Tsutomu Endo Hiroshi Kiyonari Yoshikazu Hirate Hikaru Ito Masami Kanai-Azuma Takashi Kohda Tomoko Kaneko-Ishino Fumitoshi Ishino |
| author_facet | Yoshifumi Fujioka Hirosuke Shiura Masayuki Ishii Ryuichi Ono Tsutomu Endo Hiroshi Kiyonari Yoshikazu Hirate Hikaru Ito Masami Kanai-Azuma Takashi Kohda Tomoko Kaneko-Ishino Fumitoshi Ishino |
| author_sort | Yoshifumi Fujioka |
| collection | DOAJ |
| description | Retrotransposon Gag-like (RTL) 8A, 8B and 8C are eutherian-specific genes derived from a certain retrovirus. They cluster as a triplet of genes on the X chromosome, but their function remains unknown. Here, we demonstrate that Rtl8a and Rtl8b play important roles in the brain: their double knockout (DKO) mice not only exhibit reduced social responses and increased apathy-like behaviour, but also become obese from young adulthood, similar to patients with late Prader–Willi syndrome (PWS), a neurodevelopmental genomic imprinting disorder. Mouse RTL8A/8B proteins are expressed in the prefrontal cortex and hypothalamus and localize to both the nucleus and cytoplasm of neurons, presumably due to the N-terminal nuclear localization signal-like sequence at the N-terminus. An RNAseq study in the cerebral cortex revealed reduced expression of several GABA type A receptor subunit genes in DKO, in particular Gabrb2, which encodes its β2 subunit. We confirmed the reduction of GABRB2 protein in the DKO cerebral cortex by western blotting. As GABRB2 has been implicated in the aetiology of several neurodevelopmental and neuropsychiatric disorders, it is likely that the reduction of GABRB2 is one of the major causes of the neuropsychiatric defects in the DKO mice. |
| format | Article |
| id | doaj-art-40b11efd4b144dd2bff4b3000799b4eb |
| institution | Kabale University |
| issn | 2046-2441 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | The Royal Society |
| record_format | Article |
| series | Open Biology |
| spelling | doaj-art-40b11efd4b144dd2bff4b3000799b4eb2025-01-29T00:07:10ZengThe Royal SocietyOpen Biology2046-24412025-01-0115110.1098/rsob.240279Targeting of retrovirus-derived Rtl8a/8b causes late-onset obesity, reduced social response and increased apathy-like behaviourYoshifumi Fujioka0Hirosuke Shiura1Masayuki Ishii2Ryuichi Ono3Tsutomu Endo4Hiroshi Kiyonari5Yoshikazu Hirate6Hikaru Ito7Masami Kanai-Azuma8Takashi Kohda9Tomoko Kaneko-Ishino10Fumitoshi Ishino11Department of Epigenetics, Medical Research Institute (MRI), Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, JapanDepartment of Epigenetics, Medical Research Institute (MRI), Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, JapanDepartment of Epigenetics, Medical Research Institute (MRI), Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, JapanDepartment of Epigenetics, Medical Research Institute (MRI), Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, JapanCenter for Experimental Animals, TMDU, Tokyo 113-8510, JapanLaboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo 650-0047, JapanCenter for Experimental Animals, TMDU, Tokyo 113-8510, JapanCenter for Experimental Animals, TMDU, Tokyo 113-8510, JapanCenter for Experimental Animals, TMDU, Tokyo 113-8510, JapanFaculty of Life and Environmental Sciences, University of Yamanashi, Kohfu, Yamanashi 400-8510, JapanFaculty of Nursing, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, JapanDepartment of Epigenetics, Medical Research Institute (MRI), Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, JapanRetrotransposon Gag-like (RTL) 8A, 8B and 8C are eutherian-specific genes derived from a certain retrovirus. They cluster as a triplet of genes on the X chromosome, but their function remains unknown. Here, we demonstrate that Rtl8a and Rtl8b play important roles in the brain: their double knockout (DKO) mice not only exhibit reduced social responses and increased apathy-like behaviour, but also become obese from young adulthood, similar to patients with late Prader–Willi syndrome (PWS), a neurodevelopmental genomic imprinting disorder. Mouse RTL8A/8B proteins are expressed in the prefrontal cortex and hypothalamus and localize to both the nucleus and cytoplasm of neurons, presumably due to the N-terminal nuclear localization signal-like sequence at the N-terminus. An RNAseq study in the cerebral cortex revealed reduced expression of several GABA type A receptor subunit genes in DKO, in particular Gabrb2, which encodes its β2 subunit. We confirmed the reduction of GABRB2 protein in the DKO cerebral cortex by western blotting. As GABRB2 has been implicated in the aetiology of several neurodevelopmental and neuropsychiatric disorders, it is likely that the reduction of GABRB2 is one of the major causes of the neuropsychiatric defects in the DKO mice.https://royalsocietypublishing.org/doi/10.1098/rsob.240279retrovirus-derived genesneuronal developmentsocial responseapathylate-onset obesityPrader–Willi syndrome |
| spellingShingle | Yoshifumi Fujioka Hirosuke Shiura Masayuki Ishii Ryuichi Ono Tsutomu Endo Hiroshi Kiyonari Yoshikazu Hirate Hikaru Ito Masami Kanai-Azuma Takashi Kohda Tomoko Kaneko-Ishino Fumitoshi Ishino Targeting of retrovirus-derived Rtl8a/8b causes late-onset obesity, reduced social response and increased apathy-like behaviour Open Biology retrovirus-derived genes neuronal development social response apathy late-onset obesity Prader–Willi syndrome |
| title | Targeting of retrovirus-derived Rtl8a/8b causes late-onset obesity, reduced social response and increased apathy-like behaviour |
| title_full | Targeting of retrovirus-derived Rtl8a/8b causes late-onset obesity, reduced social response and increased apathy-like behaviour |
| title_fullStr | Targeting of retrovirus-derived Rtl8a/8b causes late-onset obesity, reduced social response and increased apathy-like behaviour |
| title_full_unstemmed | Targeting of retrovirus-derived Rtl8a/8b causes late-onset obesity, reduced social response and increased apathy-like behaviour |
| title_short | Targeting of retrovirus-derived Rtl8a/8b causes late-onset obesity, reduced social response and increased apathy-like behaviour |
| title_sort | targeting of retrovirus derived rtl8a 8b causes late onset obesity reduced social response and increased apathy like behaviour |
| topic | retrovirus-derived genes neuronal development social response apathy late-onset obesity Prader–Willi syndrome |
| url | https://royalsocietypublishing.org/doi/10.1098/rsob.240279 |
| work_keys_str_mv | AT yoshifumifujioka targetingofretrovirusderivedrtl8a8bcauseslateonsetobesityreducedsocialresponseandincreasedapathylikebehaviour AT hirosukeshiura targetingofretrovirusderivedrtl8a8bcauseslateonsetobesityreducedsocialresponseandincreasedapathylikebehaviour AT masayukiishii targetingofretrovirusderivedrtl8a8bcauseslateonsetobesityreducedsocialresponseandincreasedapathylikebehaviour AT ryuichiono targetingofretrovirusderivedrtl8a8bcauseslateonsetobesityreducedsocialresponseandincreasedapathylikebehaviour AT tsutomuendo targetingofretrovirusderivedrtl8a8bcauseslateonsetobesityreducedsocialresponseandincreasedapathylikebehaviour AT hiroshikiyonari targetingofretrovirusderivedrtl8a8bcauseslateonsetobesityreducedsocialresponseandincreasedapathylikebehaviour AT yoshikazuhirate targetingofretrovirusderivedrtl8a8bcauseslateonsetobesityreducedsocialresponseandincreasedapathylikebehaviour AT hikaruito targetingofretrovirusderivedrtl8a8bcauseslateonsetobesityreducedsocialresponseandincreasedapathylikebehaviour AT masamikanaiazuma targetingofretrovirusderivedrtl8a8bcauseslateonsetobesityreducedsocialresponseandincreasedapathylikebehaviour AT takashikohda targetingofretrovirusderivedrtl8a8bcauseslateonsetobesityreducedsocialresponseandincreasedapathylikebehaviour AT tomokokanekoishino targetingofretrovirusderivedrtl8a8bcauseslateonsetobesityreducedsocialresponseandincreasedapathylikebehaviour AT fumitoshiishino targetingofretrovirusderivedrtl8a8bcauseslateonsetobesityreducedsocialresponseandincreasedapathylikebehaviour |