TRIM67 Protein Negatively Regulates Ras Activity through Degradation of 80K-H and Induces Neuritogenesis

Yaguchi, Hiroaki; Okumura, Fumihiro; Takahashi, Hidehisa; Kano, Takahiro; Kameda, Hiroyuki; Uchigashima, Motokazu; Tanaka, Shinya; Watanabe, Masahiko; Sasaki, Hidenao; Hatakeyama, Susumi

doi:10.1074/jbc.m111.307678

Cited by 52 publications

(49 citation statements)

References 47 publications

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“…In the adult brain, TRIM67 was enriched in Purkinje cells of the cerebellum, and was evident in layers 2 and 3 of the cortex ( Fig.2E), cortical axon tracts passing through the caudate putamen (CPu), and scattered cells within the midbrain (Fig.3D,E, arrowheads), but TRIM67 was not detected in the hippocampus (Fig.3F). Although TRIM67 was detected in most regions of the adult and embryonic brain, it was not detected in other tested tissues ( Fig.2F) consistent with a previous report (Yaguchi et al, 2012). Compatible with immunohistochemistry, TRIM67 protein levels in the embryo were high in the cortex, whereas in the adult brain they were high in the cerebellum.…”

Section: Generation Of Trim67 -/-Micesupporting

confidence: 91%

“…Trim9 deletion is also associated with aberrant migration, morphogenesis, and synapse organization of adult-born neurons in the murine dentate gyrus, and severe deficits in spatial learning and memory (Winkle et al, 2016). A single study has shown that TRIM67 is expressed in the mouse and human brain and regulates neuritogenesis in a mouse neuroblastoma cell line (Yaguchi et al, 2012), although its role in neurons and in vivo is unknown.…”

Section: Introductionmentioning

confidence: 99%

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The Class I E3 Ubiquitin Ligase TRIM67 Modulates Brain Development and Behavior

Boyer

Monkiewicz

Moy

et al. 2017

Preprint

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Specific class I members of the TRIM family of E3 ubiquitin ligases have been implicated in neuronal development from invertebrates to mammals. The single invertebrate class I TRIM and mammalian TRIM9 regulate axon branching and guidance in response to the axon guidance cue netrin-1, whereas mammalian TRIM46 establishes the axon initial segment. In humans, mutations in TRIM1 and TRIM18 are implicated in Optiz Syndrome, characterized by midline defects and often mild intellectual disability. TRIM67 is the most evolutionarily conserved vertebrate class I TRIM, yet is the least studied. Here we show that TRIM67 interacts with both its closest paralog TRIM9 and the netrin receptor DCC, and is differentially enriched in specific brain regions at specific developmental points. We describe the anatomical and behavioral consequences of deletion of murine Trim67. While viable, mice lacking Trim67 display severe impairments in spatial memory, cognitive flexibility, social novelty preference, muscle function and sensorimotor gating. Additionally, they exhibit abnormal anatomy of several brain regions, including the hippocampus, striatum and thalamus, as well as the corpus callosum. This study demonstrates the necessity for TRIM67 in appropriate brain development and function.SIGNIFICANCE STATEMENTAs a family, class I TRIM E3 ubiquitin ligases play important roles in neuronal development and function, potentially cooperatively. TRIM67 is the most evolutionarily conserved class I TRIM and is developmentally regulated and brain-enriched. Deletion of murine Trim67 results in malformations of a subset subcortical brain regions and of cortical and subcortical myelinated fiber tracts, as well as deficits in spatial memory, motor function, sociability and sensorimotor gating. We conclude that TRIM67 is critical for appropriate brain development and behavior, potentially downstream of the axon guidance cue netrin, and in cooperation with class I TRIM9.

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Section: Generation Of Trim67 -/-Micesupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

The Class I E3 Ubiquitin Ligase TRIM67 Modulates Brain Development and Behavior

Boyer

Monkiewicz

Moy

et al. 2017

Preprint

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“…Immunostaining of Trim67 −/− mouse brain confirmed these observations. TRIM67 is abundantly expressed in the cerebellum of both mouse and human [6,11], and immunostaining with patient CSF herein showed a similar pattern.…”

Section: Discussionmentioning

confidence: 64%

“…TRIM9 and TRIM67 have both been implicated in the morphogenesis of developing neurons or neuron-like cells [5,8,11]. To investigate a potential pathogenic mechanism and examine whether Abs affect TRIM-dependent neuronal morphogenesis, the effect of patient CSF on developing murine cortical neurons was studied in vitro .…”

Section: Resultsmentioning

confidence: 99%

TRIM9 and TRIM67 Are New Targets in Paraneoplastic Cerebellar Degeneration

Gupton

Tanji

et al. 2018

Cerebellum

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Objective: To describe autoantibodies (Abs) against tripartite motif-containing (TRIM) protein 9 and 67 in two patients with paraneoplastic cerebellar degeneration (PCD) associated with lung adenocarcinoma. Methods: Abs were characterized using immunohistochemistry, Western blotting, cultures of murine cortical, and hippocampal neurons, immunoprecipitation, mass spectrometry, knockout mice for Trim9 and 67 and cell-based assay. Control samples included sera from 63 patients with small cell lung cancer without any paraneoplastic neurological syndrome, CSF from 100 patients with autoimmune encephalitis, and CSF from 165 patients with neurodegenerative diseases. Results: We found Abs targeting TRIM9 and TRIM67 at high concentration in the serum and the cerebrospinal fluid (CSF) of a 78-year-old woman and a 65-year-old man. Both developed subacute severe cerebellar ataxia. Brain magnetic resonance imaging found no abnormality and no cerebellar atrophy. Both had CSF inflammation with mild pleiocytosis and a few oligoclonal bands. We identified a pulmonary adenocarcinoma, confirming the paraneoplastic neurological syndrome in both patients. They received immunomodulatory and cancer treatments without improvement of cerebellar ataxia, even though both were in remission of their cancer (for more than 10 years in one patient). Anti-TRIM9 and anti-TRIM67 Abs were specific to these two patients. All control serum and CSF samples tested were negative for anti-TRIM9 and 67. Interpretation: Anti-TRIM9 and anti-TRIM67 Abs appeared to be specific biomarkers of PCD and should be added to the panel of antigens tested when this is suspected.

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“…Immunoblot analysis was performed as reported previously 45 . Mutated rat BSN cDNA (c.11623C > G, p.Pro3875Ala) (BSN[Mut]), which corresponds to the mutation (c.11596C > G, p.Pro3866Ala) found in the Japanese family with PSP-like syndrome, was constructed with a QuikChange mutagenesis kit using KOD-plus-neo (KOD-401; TOYOBO) (see Supplementary Table S5).…”

Section: Genetic Methodsmentioning

confidence: 99%