Publications by authors named "N Hisamoto"

73 Publications

The Integrin Signaling Network Promotes Axon Regeneration via the Src-Ephexin-RhoA GTPase Signaling Axis.

J Neurosci 2021 Jun 7;41(22):4754-4767. Epub 2021 May 7.

Division of Biological Science, Graduate School of Science, Nagoya University, Nagoya 464-8602, Japan

Axon regeneration is an evolutionarily conserved process essential for restoring the function of damaged neurons. In hermaphrodites, initiation of axon regeneration is regulated by the RhoA GTPase-ROCK (Rho-associated coiled-coil kinase)-regulatory nonmuscle myosin light-chain phosphorylation signaling pathway. However, the upstream mechanism that activates the RhoA pathway remains unknown. Here, we show that axon injury activates TLN-1/talin via the cAMP-Epac (exchange protein directly activated by cAMP)-Rap GTPase cascade and that TLN-1 induces multiple downstream events, one of which is integrin inside-out activation, leading to the activation of the RhoA-ROCK signaling pathway. We found that the nonreceptor tyrosine kinase Src, a key mediator of integrin signaling, activates the Rho guanine nucleotide exchange factor EPHX-1/ephexin by phosphorylating the Tyr-568 residue in the autoinhibitory domain. Our results suggest that the integrin signaling network regulates axon regeneration via the Src-RhoGEF-RhoA axis. The ability of axons to regenerate after injury is governed by cell-intrinsic regeneration pathways. We have previously demonstrated that the RhoA GTPase-ROCK (Rho-associated coiled-coil kinase) pathway promotes axon regeneration by inducing MLC-4 phosphorylation. In this study, we found that axon injury activates TLN-1/talin through the cAMP-Epac (exchange protein directly activated by cAMP)-Rap GTPase cascade, leading to integrin inside-out activation, which promotes axonal regeneration by activating the RhoA signaling pathway. In this pathway, SRC-1/Src acts downstream of integrin activation and subsequently activates EPHX-1/ephexin RhoGEF by phosphorylating the Tyr-568 residue in the autoinhibitory domain. Our results suggest that the integrin signaling network regulates axon regeneration via the Src-RhoGEF-RhoA axis.
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http://dx.doi.org/10.1523/JNEUROSCI.2456-20.2021DOI Listing
June 2021

BRCA1-BARD1 Regulates Axon Regeneration in Concert with the Gqα-DAG Signaling Network.

J Neurosci 2021 Mar 16;41(13):2842-2853. Epub 2021 Feb 16.

Division of Biological Science, Graduate School of Science, Nagoya University, Nagoya 464-8602, Japan

The breast cancer susceptibility protein BRCA1 and its partner BRCA1-associated RING domain protein 1 (BARD1) form an E3-ubiquitin (Ub) ligase complex that acts as a tumor suppressor in mitotic cells. However, the roles of BRCA1-BARD1 in postmitotic cells, such as neurons, remain poorly defined. Here, we report that BRC-1 and BRD-1, the orthologs of BRCA1 and BARD1, are required for adult-specific axon regeneration, which is positively regulated by the EGL-30 Gqα-diacylglycerol (DAG) signaling pathway. This pathway is downregulated by DAG kinase (DGK), which converts DAG to phosphatidic acid (PA). We demonstrate that inactivation of DGK-3 suppresses the defect in axon regeneration, suggesting that BRC-1-BRD-1 inhibits DGK-3 function. Indeed, we show that BRC-1-BRD-1 poly-ubiquitylates DGK-3 in a manner dependent on its E3 ligase activity, causing DGK-3 degradation. Furthermore, we find that axon injury causes the translocation of BRC-1 from the nucleus to the cytoplasm, where DGK-3 is localized. These results suggest that the BRC-1-BRD-1 complex regulates axon regeneration in concert with the Gqα-DAG signaling network. Thus, this study describes a new role for breast cancer proteins in fully differentiated neurons and the molecular mechanism underlying the regulation of axon regeneration in response to nerve injury. BRCA1-BRCA1-associated RING domain protein 1 (BARD1) is an E3-ubiquitin (Ub) ligase complex acting as a tumor suppressor in mitotic cells. The roles of BRCA1-BARD1 in postmitotic cells, such as neurons, remain poorly defined. We show here that BRC-1/BRCA1 and BRD-1/BARD1 are required for adult-specific axon regeneration, a process that requires high diacylglycerol (DAG) levels in injured neurons. The DAG kinase (DGK)-3 inhibits axon regeneration by reducing DAG levels. We find that BRC-1-BRD-1 poly-ubiquitylates and degrades DGK-3, thereby keeping DAG levels elevated and promoting axon regeneration. Furthermore, we demonstrate that axon injury causes the translocation of BRC-1 from the nucleus to the cytoplasm, where DGK-3 is localized. Thus, this study describes a new role for BRCA1-BARD1 in fully-differentiated neurons.
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http://dx.doi.org/10.1523/JNEUROSCI.1806-20.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018897PMC
March 2021

F-Box Protein Promotes Axon Regeneration by Inducing Degradation of the Mad Transcription Factor.

J Neurosci 2021 03 29;41(11):2373-2381. Epub 2021 Jan 29.

Division of Biological Science, Graduate School of Science, Nagoya University, Nagoya 464-8602, Japan

In , axon regeneration is activated by a signaling cascade through the receptor tyrosine kinase (RTK) SVH-2. Axonal injury induces gene expression by degradation of the Mad-like transcription factor MDL-1. In this study, we identify the / gene encoding a protein containing F-box and F-box-associated domains as a regulator of axon regeneration in motor neurons. We find that is required for axon injury-induced expression. SDZ-33 targets MDL-1 for poly-ubiquitylation and degradation. Furthermore, we demonstrate that SDZ-33 promotes axotomy-induced nuclear degradation of MDL-1, resulting in the activation of expression in animals. These results suggest that the F-box protein is required for RTK signaling in the control of axon regeneration. In , axon regeneration is positively regulated by the growth factor SVH-1 and its receptor tyrosine kinase SVH-2. Expression of the gene is induced by axonal injury via the Ets-like transcription factor ETS-4, whose transcriptional activity is inhibited by the Mad-like transcription factor MDL-1. Axon injury leads to the degradation of MDL-1, and this is linked to the activation of ETS-4 transcriptional activity. In this study, we identify the gene encoding a protein containing an F-box domain as a regulator of axon regeneration. We demonstrate that MDL-1 is poly-ubiquitylated and degraded through the SDZ-33-mediated 26S proteasome pathway. These results reveal that an F-box protein promotes axon regeneration by degrading the Mad transcription factor.
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http://dx.doi.org/10.1523/JNEUROSCI.1024-20.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984584PMC
March 2021

Engulfment Genes Promote Neuronal Regeneration in Caenorhabditis Elegans: Two Divergent But Complementary Views.

Bioessays 2020 08 11;42(8):e1900185. Epub 2020 Jun 11.

Dept. of Biological Science, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Aichi Prefecture, Nagoya, 464-8602, Japan.

Axon regeneration is a conserved process across the animal kingdom. Recent studies using the soil worm Caenorhabditis elegans as a model system revealed that machineries regulating engulfment of dying cells also control axon regeneration and axon debris removal. In this review, the relationships between the engulfment machinery and the biological processes triggered by axon injury and subsequent axon regeneration drawn from divergent views are examined. In one study, it is found that engulfing cells directly promote axon regeneration. In this context, CED-1 (Drosophila Draper/mouse MEGF10), an engulfment protein expressed on the surface of engulfing cells, functions as a receptor for axon debris removal and as an adhesion molecule for axon regeneration. In other studies, it is shown that those engulfment genes, previously known to function within the engulfing cells for cell corpse removal, can have a cell-autonomous "non-engulfing cell" role in axon regeneration. Together, these findings suggest that engulfment genes are repurposed for neuronal regeneration by acting in both engulfing cells and regenerating neurons.
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http://dx.doi.org/10.1002/bies.201900185DOI Listing
August 2020

Clinical and endoscopic characteristics of eosinophilic esophagitis in Japan: a case-control study.

Asia Pac Allergy 2020 Apr 23;10(2):e16. Epub 2020 Apr 23.

Department of General Internal Medicine 2, Kawasaki Medical School General Medical Center, Okayama, Japan.

Background: Eosinophilic esophagitis (EoE) is an allergy-associated clinicopathologic condition gaining an increasing amount of recognition in various areas of the world. While the clinical definition and characteristics may differ depending on country and region, sufficient studies have not yet been performed in Japan.

Objective: To assess the prevalence of EoE among the Japanese population and the clinical features associated with the disease.

Methods: Endoscopic data from January 2012 to October 2018 was gathered from 9 Japanese clinical institutes. EoE, defined as esophageal mucosal eosinophilia of at least 15 eosinophils per high-power field, was determined based on esophageal biopsies. Clinical and endoscopic patterns in the cases with EoE were investigated and compared with 186 age- and sex-matched controls.

Results: From 130,013 upper endoscopic examinations, 66 cases of EoE were identified (0.051%; mean age, 45.2 years [range, 7-79 years]; 45 males). Twenty-five patients (37.9%) with EoE were diagnosed by endoscopy during a medical check-up. Patients with EoE had more symptoms (69.7% vs. 10.8%, < 0.01) such as dysphagia and food impaction, and more allergies (65.2% vs. 23.7%, < 0.01) compared with the controls. The prevalence of atrophic gastritis was lower in EoE patients than in the controls (20.0% vs. 33.3%, < 0.05).

Conclusion: The prevalence of EoE in the Japanese population was 0.051% which was comparable with previous reports in Japan. History of allergies and the absence of atrophic gastritis were associated with EoE.
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http://dx.doi.org/10.5415/apallergy.2020.10.e16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203441PMC
April 2020