CTCF loss induces giant lamellar bodies in Purkinje cell dendrites

Abstract Loss of Purkinje cells (PCs) in the cerebellum causes severe motor deficits. The peculiar lamellar structures known as “giant lamellar bodies” (GLBs) have been reported in PCs of patients with Werdnig-Hoffman disease, 13q deletion syndrome, and Krabbe’s disease. GLBs are localized to PC dendrites and are 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 the CCCTC-binding factor (CTCF) was deleted. CTCF orchestrates gene expression by organizing the three-dimensional chromatin structure. The mouse model showed progressive motor dysfunction and abnormal dendritic morphology in PCs, including dendritic self-avoidance defects and proximal shift in the climbing fibre innervation territory on PC dendrites. GLBs were not clearly found in PC dendrites at infancy but instead developed with age. In conjunction with GLB development, 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. Thus, our results are the first experimental demonstration that GLBs represent a pathological alteration of PCs and suggest different genetic backgrounds involved in the induction of GLBs.