Effects of NDRG1 family proteins on photoreceptor outer segment morphology in zebrafish

Takita, Shimpei; Wada, Yasutaka; Kawamura, Sadao

doi:10.1038/srep36590

Cited by 9 publications

(14 citation statements)

References 24 publications

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“…For example, NDRG1 has been reported to have an association with stress response, cell proliferation, and differentiation (49)(50)(51); NDRG1 has been identified as a metastasis suppressor in a variety of cancers (52); and NDRG1 knockout mice experience autonomous dysfunction of Schwann cells and exhibit progressive demyelination in peripheral nerves (53). In zebrafish, there are two orthologs of the mammalian NDRG1, which are termed NDRG1a (consisting of two variants, NDRG1a-1 and NDRG1a-2) and NDRG1b (54). The two splice variants of NDRG1a are different only at their N-terminal amino acid sequences.…”

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confidence: 99%

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Zebrafish NDRG1a Negatively Regulates IFN Induction by Promoting the Degradation of IRF7

Wang

et al. 2019

The Journal of Immunology

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Viral infection activates the transcription factor IFN regulatory factor 7 (IRF7), which plays a critical role in the induction of IFNs and innate antiviral immune response. How virus-induced IFN signaling is controlled in fish is not fully understood. In this study, we demonstrate that N-myc downstream-regulated gene 1a (NDRG1a) in zebrafish plays a role as a negative regulator for virustriggered IFN induction. First, the activation of the IFN promoter stimulated by the polyinosinic-polycytidylic acid or spring viremia of carp virus was decreased by the overexpression of NDRG1a. Second, NDRG1a interacted with IRF7 and blocked the IFN transcription activated by IRF7. Furthermore, NDRG1a was phosphorylated by TANK-binding kinase 1 (TBK1) and promoted the K48-linked ubiquitination and degradation of IRF7. Finally, the overexpression of NDRG1a blunted the transcription of several IFN-stimulated genes, resulting in the host cells becoming susceptible to spring viremia of carp virus infection. Our findings suggest that fish NDRG1a negatively regulates the cellular antiviral response by targeting IRF7 for ubiquitination and degradation, providing insights into the novel role of NDRG1a on the innate antiviral immune response in fish.

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confidence: 99%

“…The two splice variants of NDRG1a are different only at their N-terminal amino acid sequences. Recently, a study has reported that NDRG1 family proteins are involved in forming a normal outer segment shape in zebrafish photoreceptors (54). However, how NDRG1 is involved in antiviral immune response, if it is at all, is still unclear.…”

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confidence: 99%

Zebrafish NDRG1a Negatively Regulates IFN Induction by Promoting the Degradation of IRF7

Wang

et al. 2019

The Journal of Immunology

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“…To explore whether the NDRG family member(s) contribute to photoreceptor-specific cell loss, we originally hypothesized that NDRG1 was the putative candidate, considering that NDRG1 is the only NDRG subtype currently found expression in the retina, and that NDRG1 is involved in forming a normal morphological shape in zebrafish photoreceptors 19 . Accordingly, we indeed detected major distribution of NDRG1 in the inner segment/outer segment (IS/OS) of photoreceptor cells 29 , while NDRG1 was also present in the inner plexiform layer (IPL)/ganglion cell layer (GCL), as well as the outer plexiform layer (OPL) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Accumulating data also suggest organ/tissue-specific biological function of NDRGs in development and postnatal homeostasis, among which NDRG1, 2, and 4 are widely distributed in the nervous system and are involved in neural degenerative diseases 15 – 17 . Particularly, for the specialized neurons in the vertebrate retina, which include rod and cone photoreceptors, interneurons, and RGCs 18 , only NDRG1 has been documented expression with contributions to morphology in zebrafish photoreceptors, while NDRG2 was detected in murine astrocytes except the proliferative retinal Müller glia 19 , 20 . At the present time, it is unclear as to whether existence and altered level(s) of certain NDRG subtype(s) correlate with functional outcomes in retinal damaging conditions, and whether the effects are cell-type specific.…”

Section: Introductionmentioning

confidence: 99%

NDRG2 suppression as a molecular hallmark of photoreceptor-specific cell death in the mouse retina

Sui

Wang

et al. 2018

Cell Death Discov.

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Photoreceptor cell death is recognized as the key pathogenesis of retinal degeneration, but the molecular basis underlying photoreceptor-specific cell loss in retinal damaging conditions is virtually unknown. The N-myc downstream regulated gene (NDRG) family has recently been reported to regulate cell viability, in particular NDRG1 has been uncovered expression in photoreceptor cells. Accordingly, we herein examined the potential roles of NDRGs in mediating photoreceptor-specific cell loss in retinal damages. By using mouse models of retinal degeneration and the 661 W photoreceptor cell line, we showed that photoreceptor cells are indeed highly sensitive to light exposure and the related oxidative stress, and that photoreceptor cells are even selectively diminished by phototoxins of the alkylating agent N-Methyl-N-nitrosourea (MNU). Unexpectedly, we discovered that of all the NDRG family members, NDRG2, but not the originally hypothesized NDRG1 or other NDRG subtypes, was selectively expressed and specifically responded to retinal damaging conditions in photoreceptor cells. Furthermore, functional experiments proved that NDRG2 was essential for photoreceptor cell viability, which could be attributed to NDRG2 control of the photo-oxidative stress, and that it was the suppression of NDRG2 which led to photoreceptor cell loss in damaging conditions. More importantly, NDRG2 preservation contributed to photoreceptor-specific cell maintenance and retinal protection both in vitro and in vivo. Our findings revealed a previously unrecognized role of NDRG2 in mediating photoreceptor cell homeostasis and established for the first time the molecular hallmark of photoreceptor-specific cell death as NDRG2 suppression, shedding light on improved understanding and therapy of retinal degeneration.

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“…Identification of an eys tv predominantly expressed in the adult zebrafish eye and its novel splice variants by CAGE, cloning, and RNA-seq Orthologs of human EYS gene are absent in mice and rats but are conserved across many other species, including the freshwater teleost, zebrafish. Because zebrafish husbandry is easy, they are widely used for genetic studies (16). Therefore, we chose zebrafish as a model organism to obtain insights into the functions of EYS gene in vertebrate photoreceptors (10)(11)(12).…”

Section: Analysis Of Expression Of the 59 And 39 Portions Of Eys Tranmentioning

confidence: 99%

Intra‐ and interspecies comparison of EYS transcripts highlights its characteristics in the eye

2019

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Inherited mutations in the eyes shut homolog (EYS) gene cause retinitis pigmentosa. Although knock out of eys in zebrafish is pathogenic, the molecular function of EYS in vertebrate photoreceptors is poorly understood. Here, we show that the 5′ portion of EYS is eye‐specific across vertebrates. We previously determined that a 3′ fragment of EYS with an unknown transcription start site is expressed in human dermal fibroblasts (HDF). To obtain insights into the molecular function of EYS in vertebrate photoreceptors, we extensively analyzed EYS (eys) expression in the human fibroblast cell line HDF‐adult (HDF‐a), the Y79 retinoblastoma cell line, and in zebrafish eyes using rapid amplification of cDNA end, cap analysis of gene expression, RNA sequencing, and RT‐PCR. In HDF‐a cells, we identified a novel transcript variant (tv), tv5, transcribed from exon 37. In Y79 cells and zebrafish eyes, EYS (eys) was predominantly transcribed from exon 1 or 2, whereas it was transcribed exclusively from exon 37 in HDF‐a cells. In the zebrafish eye, there were splice variants that introduced stop codons, resulting in complete loss of the 3′ portion of the RNA. These comparative approaches indicate that the 5′ portion of the EYS (eys) mRNA appears to be photoreceptor‐specific and that the compositions of the deduced EYS proteins in the eye are well‐conserved across vertebrates.—Takita, S., Miyamoto‐Matsui, K., Seko, Y. Intra‐ and interspecies comparison of EYS transcripts highlights its characteristics in the eye. FASEB J. 33, 9422–9433 (2019). http://www.fasebj.org

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Effects of NDRG1 family proteins on photoreceptor outer segment morphology in zebrafish

Cited by 9 publications

References 24 publications

Zebrafish NDRG1a Negatively Regulates IFN Induction by Promoting the Degradation of IRF7

Zebrafish NDRG1a Negatively Regulates IFN Induction by Promoting the Degradation of IRF7

NDRG2 suppression as a molecular hallmark of photoreceptor-specific cell death in the mouse retina

Intra‐ and interspecies comparison of EYS transcripts highlights its characteristics in the eye

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