CTCF loss induces giant lamellar bodies in Purkinje cell dendrites
Abstract CCCTC-binding factor (CTCF) has a key role in higher-order chromatin architecture that is important for establishing and maintaining cell identity by controlling gene expression. In the mature cerebellum, CTCF is highly expressed in Purkinje cells (PCs) as compared with other cerebellar neu...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-11-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-022-01478-6 |
| _version_ | 1811207620274421760 |
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| author | Teruyoshi Hirayama Yuuki Kadooka Etsuko Tarusawa Sei Saitoh Hisako Nakayama Natsumi Hoshino Soichiro Nakama Takahiro Fukuishi Yudai Kawanishi Hiroki Umeshima Koichi Tomita Yumiko Yoshimura Niels Galjart Kouichi Hashimoto Nobuhiko Ohno Takeshi Yagi |
| author_facet | Teruyoshi Hirayama Yuuki Kadooka Etsuko Tarusawa Sei Saitoh Hisako Nakayama Natsumi Hoshino Soichiro Nakama Takahiro Fukuishi Yudai Kawanishi Hiroki Umeshima Koichi Tomita Yumiko Yoshimura Niels Galjart Kouichi Hashimoto Nobuhiko Ohno Takeshi Yagi |
| author_sort | Teruyoshi Hirayama |
| collection | DOAJ |
| description | Abstract CCCTC-binding factor (CTCF) has a key role in higher-order chromatin architecture that is important for establishing and maintaining cell identity by controlling gene expression. In the mature cerebellum, CTCF is highly expressed in Purkinje cells (PCs) as compared with other cerebellar neurons. The cerebellum plays an important role in motor function by regulating PCs, which are the sole output neurons, and defects in PCs cause motor dysfunction. However, the role of CTCF in PCs has not yet been explored. Here we found that the absence of CTCF in mouse PCs led to progressive motor dysfunction and abnormal dendritic morphology in those cells, which included dendritic self-avoidance defects and a proximal shift in the climbing fibre innervation territory on PC dendrites. Furthermore, we found the peculiar lamellar structures known as “giant lamellar bodies” (GLBs), which have been reported in PCs of patients with Werdnig-Hoffman disease, 13q deletion syndrome, and Krabbe disease. GLBs are localized to PC dendrites and are assumed to be associated with neurodegeneration. They have been noted, however, only in case reports following autopsy, and reports of their existence have been very limited. Here we show that GLBs were reproducibly formed in PC dendrites of a mouse model in which CTCF was deleted. GLBs were not noted in PC dendrites at infancy but instead developed over time. In conjunction with GLB development in PC dendrites, the endoplasmic reticulum was almost absent around the nuclei, the mitochondria were markedly swollen and their cristae had decreased drastically, and almost all PCs eventually disappeared as severe motor deficits manifested. Our results revealed the important role of CTCF during normal development and in maintaining PCs and provide new insights into the molecular mechanism of GLB formation during neurodegenerative disease. |
| first_indexed | 2024-04-12T04:07:37Z |
| format | Article |
| id | doaj.art-a72517b6649347dfb51706d49c79da9c |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-04-12T04:07:37Z |
| publishDate | 2022-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-a72517b6649347dfb51706d49c79da9c2022-12-22T03:48:35ZengBMCActa Neuropathologica Communications2051-59602022-11-0110111710.1186/s40478-022-01478-6CTCF loss induces giant lamellar bodies in Purkinje cell dendritesTeruyoshi Hirayama0Yuuki Kadooka1Etsuko Tarusawa2Sei Saitoh3Hisako Nakayama4Natsumi Hoshino5Soichiro Nakama6Takahiro Fukuishi7Yudai Kawanishi8Hiroki Umeshima9Koichi Tomita10Yumiko Yoshimura11Niels Galjart12Kouichi Hashimoto13Nobuhiko Ohno14Takeshi Yagi15KOKORO-Biology Group, Laboratories for Integrated Biology, Graduate School of Frontier Biosciences, Osaka UniversityKOKORO-Biology Group, Laboratories for Integrated Biology, Graduate School of Frontier Biosciences, Osaka UniversityKOKORO-Biology Group, Laboratories for Integrated Biology, Graduate School of Frontier Biosciences, Osaka UniversitySection of Electron Microscopy, Supportive Center for Brain Research, National Institute for Physiological SciencesDepartment of Physiology, Division of Neurophysiology, School of Medicine, Tokyo Women’s Medical UniversityKOKORO-Biology Group, Laboratories for Integrated Biology, Graduate School of Frontier Biosciences, Osaka UniversityDepartment of Anatomy and Developmental Neurobiology, Tokushima University Graduate School of Medical SciencesDepartment of Anatomy and Developmental Neurobiology, Tokushima University Graduate School of Medical SciencesDepartment of Anatomy and Developmental Neurobiology, Tokushima University Graduate School of Medical SciencesDepartment of Anatomy and Developmental Neurobiology, Tokushima University Graduate School of Medical SciencesDepartment of Anatomy and Developmental Neurobiology, Tokushima University Graduate School of Medical SciencesSection of Visual Information Processing, National Institute for Physiological Sciences, National Institutes of Natural SciencesDepartment of Cell Biology, Erasmus University Medical CenterDepartment of Neurophysiology, Graduate School of Biomedical and Health Sciences, Hiroshima UniversityDivision of Ultrastructural Research, National Institute for Physiological SciencesKOKORO-Biology Group, Laboratories for Integrated Biology, Graduate School of Frontier Biosciences, Osaka UniversityAbstract CCCTC-binding factor (CTCF) has a key role in higher-order chromatin architecture that is important for establishing and maintaining cell identity by controlling gene expression. In the mature cerebellum, CTCF is highly expressed in Purkinje cells (PCs) as compared with other cerebellar neurons. The cerebellum plays an important role in motor function by regulating PCs, which are the sole output neurons, and defects in PCs cause motor dysfunction. However, the role of CTCF in PCs has not yet been explored. Here we found that the absence of CTCF in mouse PCs led to progressive motor dysfunction and abnormal dendritic morphology in those cells, which included dendritic self-avoidance defects and a proximal shift in the climbing fibre innervation territory on PC dendrites. Furthermore, we found the peculiar lamellar structures known as “giant lamellar bodies” (GLBs), which have been reported in PCs of patients with Werdnig-Hoffman disease, 13q deletion syndrome, and Krabbe disease. GLBs are localized to PC dendrites and are assumed to be associated with neurodegeneration. They have been noted, however, only in case reports following autopsy, and reports of their existence have been very limited. Here we show that GLBs were reproducibly formed in PC dendrites of a mouse model in which CTCF was deleted. GLBs were not noted in PC dendrites at infancy but instead developed over time. In conjunction with GLB development in PC dendrites, the endoplasmic reticulum was almost absent around the nuclei, the mitochondria were markedly swollen and their cristae had decreased drastically, and almost all PCs eventually disappeared as severe motor deficits manifested. Our results revealed the important role of CTCF during normal development and in maintaining PCs and provide new insights into the molecular mechanism of GLB formation during neurodegenerative disease.https://doi.org/10.1186/s40478-022-01478-6CCCTC-binding factorGiant lamellar bodyPurkinje cellNeurodegenerationMotor dysfunction |
| spellingShingle | Teruyoshi Hirayama Yuuki Kadooka Etsuko Tarusawa Sei Saitoh Hisako Nakayama Natsumi Hoshino Soichiro Nakama Takahiro Fukuishi Yudai Kawanishi Hiroki Umeshima Koichi Tomita Yumiko Yoshimura Niels Galjart Kouichi Hashimoto Nobuhiko Ohno Takeshi Yagi CTCF loss induces giant lamellar bodies in Purkinje cell dendrites Acta Neuropathologica Communications CCCTC-binding factor Giant lamellar body Purkinje cell Neurodegeneration Motor dysfunction |
| title | CTCF loss induces giant lamellar bodies in Purkinje cell dendrites |
| title_full | CTCF loss induces giant lamellar bodies in Purkinje cell dendrites |
| title_fullStr | CTCF loss induces giant lamellar bodies in Purkinje cell dendrites |
| title_full_unstemmed | CTCF loss induces giant lamellar bodies in Purkinje cell dendrites |
| title_short | CTCF loss induces giant lamellar bodies in Purkinje cell dendrites |
| title_sort | ctcf loss induces giant lamellar bodies in purkinje cell dendrites |
| topic | CCCTC-binding factor Giant lamellar body Purkinje cell Neurodegeneration Motor dysfunction |
| url | https://doi.org/10.1186/s40478-022-01478-6 |
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