气候变化领域集成服务门户(CCPortal): A Kalirin missense mutation enhances dendritic RhoA signaling and leads to regression of cortical dendritic arbors across development

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DOI	10.1073/pnas.2022546118
	A Kalirin missense mutation enhances dendritic RhoA signaling and leads to regression of cortical dendritic arbors across development
	Grubisha M.J.; Sun T.; Eisenman L.; Erickson S.L.; Chou S.-Y.; Helmer C.D.; Trudgen M.T.; Ding Y.; Homanics G.E.; Penzes P.; Wills Z.P.; Sweet R.A.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:49
英文摘要	Normally, dendritic size is established prior to adolescence and then remains relatively constant into adulthood due to a homeostatic balance between growth and retraction pathways. However, schizophrenia is characterized by accelerated reductions of cerebral cortex gray matter volume and onset of clinical symptoms during adolescence, with reductions in layer 3 pyramidal neuron dendritic length, complexity, and spine density identified in multiple cortical regions postmortem. Nogo receptor 1 (NGR1) activation of the GTPase RhoA is a major pathway restricting dendritic growth in the cerebral cortex. We show that the NGR1 pathway is stimulated by OMGp and requires the Rho guanine nucleotide exchange factor Kalirin-9 (KAL9). Using a genetically encoded RhoA sensor, we demonstrate that a naturally occurring missense mutation in Kalrn, KAL-PT, that was identified in a schizophrenia cohort, confers enhanced RhoA activitation in neuronal dendrites compared to wild-type KAL. In mice containing this missense mutation at the endogenous locus, there is an adolescent-onset reduction in dendritic length and complexity of layer 3 pyramidal neurons in the primary auditory cortex. Spine density per unit length of dendrite is unaffected. Early adult mice with these structural deficits exhibited impaired detection of short gap durations. These findings provide a neuropsychiatric model of disease capturing how a mild genetic vulnerability may interact with normal developmental processes such that pathology only emerges around adolescence. This interplay between genetic susceptibility and normal adolescent development, both of which possess inherent individual variability, may contribute to heterogeneity seen in phenotypes in human neuropsychiatric disease. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Adolescence; Dendrite; Kalirin; NGR1
语种	英语
scopus关键词	Nogo receptor 1; RhoA guanine nucleotide binding protein; glycosylphosphatidylinositol anchored protein; guanine nucleotide exchange factor; kalirin protein, mouse; myelin protein; Nogo receptor 1; Omg protein, mouse; Rtn4r protein, mouse; adult; animal cell; animal experiment; animal tissue; Article; auditory cortex; brain cortex; cell growth; cell structure; controlled study; dendrite; dendritic cell; enzyme activation; female; gene; gene locus; genetic association; genetic heterogeneity; genetic susceptibility; genetic variability; Kalrn gene; male; missense mutation; mouse; nonhuman; phenotype; remission; schizophrenia; signal transduction; animal; brain cortex; CRISPR Cas system; cytology; dendrite; gene expression regulation; genetics; genotype; human; metabolism; missense mutation; nerve cell; physiology; sexual maturation; signal transduction; transgenic mouse; Animals; Cerebral Cortex; CRISPR-Cas Systems; Dendrites; Gene Expression Regulation, Developmental; Genotype; GPI-Linked Proteins; Guanine Nucleotide Exchange Factors; Humans; Mice; Mice, Transgenic; Mutation, Missense; Myelin Proteins; Neurons; Nogo Receptor 1; Sexual Maturation; Signal Transduction
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/250958
作者单位	Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States; Department of Biostatistics, University of PittsburghPA 15261, United States; Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15261, United States; Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, United States; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, United States; Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States; Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States
推荐引用方式 GB/T 7714	Grubisha M.J.,Sun T.,Eisenman L.,et al. A Kalirin missense mutation enhances dendritic RhoA signaling and leads to regression of cortical dendritic arbors across development[J],2021,118(49).
APA	Grubisha M.J..,Sun T..,Eisenman L..,Erickson S.L..,Chou S.-Y..,...&Sweet R.A..(2021).A Kalirin missense mutation enhances dendritic RhoA signaling and leads to regression of cortical dendritic arbors across development.Proceedings of the National Academy of Sciences of the United States of America,118(49).
MLA	Grubisha M.J.,et al."A Kalirin missense mutation enhances dendritic RhoA signaling and leads to regression of cortical dendritic arbors across development".Proceedings of the National Academy of Sciences of the United States of America 118.49(2021).