Keisuke Fujioka, Takashi Nagai, Tomoki Hattori, Shoji Kagami, Koji Yasutomo, Niels Galjart, Teruyoshi Hirayama, Hiroshi Kawachi and Maki Urushihara : Renin-angiotensin blockade ameliorates the progression of glomerular injury in podocyte-specific Ctcf knockout mice., Nephrology, 29, 12, 815-824, 2024.
(要約)
These results suggest that RAS is involved in the development of glomerulopathy in podocyte-specific Ctcf knockout mice. Elucidation of the pathophysiology of podocyte-specific Ctcf knockout mice may provide new insights into the relationship between podocyte injury and chronic glomerulonephritis.
H Kobayashi, K Takemoto, M Sanbo, M Hirabayashi, T Hirabayashi, Teruyoshi Hirayama, H Kiyonari, T Abe and T Yagi : Isoform requirement of clustered protecadherin for preventing neuronal apoptosis and neonatal lethality, iScience, 6, 1, 105766, 2023.
(要約)
Clustered protocadherin is a family of cell-surface recognition molecules implicated in neuronal connectivity that has a diverse isoform repertoire and homophilic binding specificity. Mice have 58 isoforms, encoded by , , and gene clusters, and mutant mice lacking all isoforms died after birth, displaying massive neuronal apoptosis and synapse loss. The current hypothesis is that the three specific γC-type isoforms, especially γC4, are essential for the phenotype, raising the question about the necessity of isoform diversity. We generated mutant mice that expressed the three γC-type isoforms but lacked all the other 55 isoforms. The mutants died immediately after birth, showing massive neuronal death, and or expression did not prevent apoptosis. Restoring the - and -clusters with the three alleles rescued the phenotype, suggesting that along with the three γC-type isoforms, other isoforms are also required for the survival of neurons and individual mice.
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.
(キーワード)
CCCTC-binding factor / Giant lamellar body / Motor dysfunction / Neurodegeneration / Purkinje cell
A. Uyeda, Teruyoshi Hirayama, S. Hattori, T. Myakawa, T. Yagi, N. Yamamoto and N. Sugo : Suppression of DNA Double-Strand Break Formation by DNA Polymerase β in Active DNA Demethylation Is Required for Development of Hippocampal Pyramidal Neurons. J, The Journal of Neuroscience, 40, 47, 9012-9027, 2020.
(要約)
Genome stability is essential for brain development and function, as mutations during neuronal development cause psychiatric disorders. However, the contribution of DNA repair to genome stability in neurons remains elusive. Here, we demonstrate that the base excision repair protein DNA polymerase β (Polβ) is involved in hippocampal pyramidal neuron differentiation via a TET-mediated active DNA demethylation during early postnatal stages using β mice of either sex, in which forebrain postmitotic excitatory neurons lack Polβ expression. Polβ deficiency induced extensive DNA double-strand breaks (DSBs) in hippocampal pyramidal neurons, but not dentate gyrus granule cells, and to a lesser extent in neocortical neurons, during a period in which decreased levels of 5-methylcytosine and 5-hydroxymethylcytosine were observed in genomic DNA. Inhibition of the hydroxylation of 5-methylcytosine by expression of microRNAs miR-29a/b-1 diminished DSB formation. Conversely, its induction by TET1 catalytic domain overexpression increased DSBs in neocortical neurons. Furthermore, the damaged hippocampal neurons exhibited aberrant neuronal gene expression profiles and dendrite formation, but not apoptosis. Comprehensive behavioral analyses revealed impaired spatial reference memory and contextual fear memory in adulthood. Thus, Polβ maintains genome stability in the active DNA demethylation that occurs during early postnatal neuronal development, thereby contributing to differentiation and subsequent learning and memory. Increasing evidence suggests that mutations during neuronal development cause psychiatric disorders. However, strikingly little is known about how DNA repair is involved in neuronal differentiation. We found that Polβ, a component of base excision repair, is required for differentiation of hippocampal pyramidal neurons in mice. Polβ deficiency transiently led to increased DNA double-strand breaks, but not apoptosis, in early postnatal hippocampal pyramidal neurons. This aberrant double-strand break formation was attributed to active DNA demethylation as an epigenetic regulation. Furthermore, the damaged neurons exhibited aberrant gene expression profiles and dendrite formation, resulting in impaired learning and memory in adulthood. Thus, these findings provide new insight into the contribution of DNA repair to the neuronal genome in early brain development.
H. Asai, N. Ohkawa, Y. Saitoh, K. Ghandour, E. Murayama, H. Nishizono, M. Matsuo, Teruyoshi Hirayama, R. Kaneko, S. Muramatsu, T. Yagi and K. Inokuchi : Pcdhβ deficiency affects hippocampal CA1 ensemble activity and contextual fear discrimination, Molecular Brain, 13, 1, 7, 2020.
(要約)
Clustered protocadherins (Pcdhs), a large group of adhesion molecules, are important for axonal projections and dendritic spread, but little is known about how they influence neuronal activity. The Pcdhβ cluster is strongly expressed in the hippocampus, and in vivo Ca imaging in Pcdhβ-deficient mice revealed altered activity of neuronal ensembles but not of individual cells in this region in freely moving animals. Specifically, Pcdhβ deficiency increased the number of large-size neuronal ensembles and the proportion of cells shared between ensembles. Furthermore, Pcdhβ-deficient mice exhibited reduced repetitive neuronal population activity during exploration of a novel context and were less able to discriminate contexts in a contextual fear conditioning paradigm. These results suggest that one function of Pcdhβs is to modulate neural ensemble activity in the hippocampus to promote context discrimination.
(キーワード)
Animals / CA1 Region, Hippocampal / Cadherins / Calcium / Conditioning, Classical / Discrimination Learning / Electroshock / Exploratory Behavior / Fear / Genes, Reporter / Genetic Vectors / Male / Mice / Mice, Knockout / Microscopy, Fluorescence / Neurons / Open Field Test / Protein Isoforms
M Alvarez-Saavedra, K Yan, Y Repentigny De, LE Hashem, N Chaudary, S Sarwar, D Yang, I Ioshikhes, R Kothary, Teruyoshi Hirayama, T Yagi and DJ Picketts : Snf2h Drives Chromatin Remodeling to Prime Upper Layer Cortical Neuron Development, Frontiers in Molecular Neuroscience, 12, 243, 2019.
(要約)
Alterations in the homeostasis of either cortical progenitor pool, namely the apically located radial glial (RG) cells or the basal intermediate progenitors (IPCs) can severely impair cortical neuron production. Such changes are reflected by microcephaly and are often associated with cognitive defects. Genes encoding epigenetic regulators are a frequent cause of intellectual disability and many have been shown to regulate progenitor cell growth, including our inactivation of the gene encoding Snf2l, which is one of two mammalian orthologs. Loss of the Snf2l protein resulted in dysregulation of Foxg1 and IPC proliferation leading to macrocephaly. Here we show that inactivation of the closely related gene encoding the Snf2h chromatin remodeler is necessary for embryonic IPC expansion and subsequent specification of callosal projection neurons. Telencephalon-specific cKO embryos have impaired cell cycle kinetics and increased cell death, resulting in fewer Tbr2+ and FoxG1+ IPCs by mid-neurogenesis. These deficits give rise to adult mice with a dramatic reduction in Satb2+ upper layer neurons, and partial agenesis of the corpus callosum. Mice survive into adulthood but molecularly display reduced expression of the clustered protocadherin genes that may further contribute to altered dendritic arborization and a hyperactive behavioral phenotype. Our studies provide novel insight into the developmental function of Snf2h-dependent chromatin remodeling processes during brain development.
Z Shao, H Noh, WB Kim, P Ni, C Nguyen, SE Cote, E Noyes, J Zhao, T Parsons, JM Park, K Zheng, JJ Park, JT Coyle, DR Weinberger, RE Straub, KF Berman, J Apud, D Ongur, BM Cohen, DL McPhie, JL Rapoport, RH Perlis, TA Lanz, S Xi, C Yin, W Huang, Teruyoshi Hirayama, E Fukuda, T Yagi, S Ghosh, KC Eggan, H-Y Kim, LM Eisenberg, A Moghadam, P Stanton, J-H Cho and S Chung : Dysregulated protocadherin-pathway activity as an intrinsic defect in iPSC-derived cortical interneurons from patients with schizophrenia, Nature Neuroscience, 22, 2, 229-242, 2019.