Hiroki Umeshima, Teruyoshi Hirayama, Ryosuke Adachi and Koichi Tomita : Distinct cellular and subcellular distributions of the alpha and beta isoforms of Heat Shock Protein 90 in the mouse cerebral cortex, Gene Expression Patterns, 57, 119412, 2026.
(Summary)
Heat Shock Protein (HSP) 90 is a molecular chaperone that contributes to a broad range of cellular processes in nearly all tissues including the brain. HSP90 has two isoforms, namely HSP90α and HSP90β, that have highly similar amino-acid sequences and have therefore been assumed to perform redundant functions, although their roles may be distinct in certain cellular contexts. In both the developing brain and adult brain, it remains unclear whether HSP90α and HSP90β have unique functions. Here we demonstrate that these two isoforms are differentially distributed in the mouse cerebral cortex, as evidenced by immunofluorescence staining, fluorescence in situ hybridization, and single-cell RNA sequencing data. HSP90α was strongly expressed in layer 5 excitatory neurons, inhibitory neurons across all layers, and a subset of oligodendrocytes. In addition to the populations expressing HSP90α, HSP90β was strongly expressed in layer 6 neurons. Moreover, HSP90β was preferentially enriched in distal portions of neurites compared with HSP90α. These results suggest unique roles for HSP90α and HSP90β in certain cell types of the cerebral cortex.
Loic Broix, Rohini Roy, Belal Shohayeb, Ikumi Oomoto, Hiroki Umeshima and Ohtan Dan Wang : m6A RNA methylation-mediated control of global APC expression is required for local translation of β-actin and axon development, Cell Reports, 44, 6, 115727, 2025.
(Summary)
The spatial regulation of mRNAs in neurons, including their localization and translation, is controlled by RNA-binding proteins and is critical for neuronal development. In this study, we present evidence that the multifunctional RNA-binding protein adenomatous polyposis coli (APC) is encoded by an mRNA modified with N6-methyladenosine (m6A). This modification facilitates the translation of APC in neuronal somata via YTH domain-containing family (YTHDF) m6A reader proteins. Disrupted APC expression, caused by reduced expression of the m6A writer METTL14 or reader YTHDF1, or by overexpression of METTL14 mutants carrying human missense mutations linked to autism and schizophrenia, impairs the transport and local translation of APC-regulated target mRNA β-actin in axons and growth cones. Such disruptions consequently hinder axon development both in vitro and in vivo. These findings reveal a mechanism by which m6A-regulated global expression of the RNA-binding protein APC governs axonal mRNA translation and development.
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.
(Keyword)
CCCTC-binding factor / Giant lamellar body / Motor dysfunction / Neurodegeneration / Purkinje cell
Analysis of the Mechanism of Neurological Symptoms Caused by Metabolic Dysfunction-Associated Steatohepatitis from the Perspective of Multi-Organ Crosstalk (Project/Area Number: 25K09812 )
Effects of RNA modification and local translation in the growth cone on neural circuit formation (Project/Area Number: 18K06464 )