CTCF loss induces giant lamellar bodies in Purkinje cell dendrites

Journal Acta Neuropathol. Commun. 10(1):172 (2022)
Title CTCF loss induces giant lamellar bodies in Purkinje cell dendrites
Laboratory KOKORO-Biology Group〈Prof. YAGI Takeshi〉

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.


Teruyoshi Hirayama (1, 2), Yuuki Kadooka (1), Etsuko Tarusawa (1), Sei Saitoh (3, 4), Hisako Nakayama (5, 6), Natsumi Hoshino (1), Soichiro Nakama (2), Takahiro Fukuishi (2), Yudai Kawanishi (2), Hiroki Umeshima (2), Koichi Tomita (2), Yumiko Yoshimura (7, 8), Niels Galjart (9), Kouichi Hashimoto (6), Nobuhiko Ohno (10, 9), Takeshi Yagi (1)

  1. KOKORO-Biology Group, Laboratories for Integrated Biology, Graduate School of Frontier Biosciences, Osaka University, Suita, 565-0871, Japan.Department of Anatomy and Developmental Neurobiology, Tokushima University Graduate School of Medical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
  2. Section of Electron Microscopy, Supportive Center for Brain Research, National Institute for Physiological Sciences, Okazaki, 444-8787, Japan.
  3. Department of Anatomy II and Cell Biology, Fujita Health University School of Medicine, 1-98 Dengakubo, Kutsukake-cho, Toyoake, 470-1192, Japan.
  4. Department of Physiology, Division of Neurophysiology, School of Medicine, Tokyo Women's Medical University, Tokyo, 162-8666, Japan.
  5. Department of Neurophysiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
  6. Section of Visual Information Processing, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Aichi, 444-8585, Japan.
  7. Department of Physiological Sciences, The Graduate University for Advanced Studies, Okazaki, Aichi, 444-8585, Japan.
  8. Department of Cell Biology, Erasmus University Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.
  9. Division of Ultrastructural Research, National Institute for Physiological Sciences, Okazaki, 444-8585, Japan.
  10. Department of Anatomy, Division of Histology and Cell Biology, Jichi Medical University, Shimotsuke, 329-0498, Japan.
PubMed 36447271