Nel positively regulates the genesis of retinal ganglion cells by promoting their differentiation and survival during development

Nakamoto, Chizu; Kuan, Soh-Leh; Findlay, Amy S.; Durward, Elaine; Ouyang, Zhufeng; Zakrzewska, E.D.; Endo, Tamio; Nakamoto, Masaru

doi:10.1091/mbc.e13-08-0453

Cited by 6 publications

(15 citation statements)

References 59 publications

(56 reference statements)

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“…Nel ‐like2 is predominantly expressed in the nervous system and has been implicated in neural development . Recently, we showed that chicken Nel (NELL2) regulates retinal axon guidance and production of retinal ganglion cells during development …”

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confidence: 99%

“…Recently, we showed that chicken Nel (NELL2) regulates retinal axon guidance (15) and production of retinal ganglion cells during development. (16) Expression of NELL1 and NELL2 genes has been studied in human lymphoma, in cancers of the central nervous system, prostate, and bladder, and in cancer cell lines. (17)(18)(19)(20) Furthermore, NELL1 and NELL2 expression was reported in adult and embryonic normal kidney.…”

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confidence: 99%

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Expression and regulatory effects on cancer cell behavior of NELL1 and NELL2 in human renal cell carcinoma

et al. 2015

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Neural epidermal growth factor-like like (NELL) 1 and 2 constitute a family of multimeric and multimodular extracellular glycoproteins. Although the osteogenic effects of NELL1 and functions of NELL2 in neural development have been reported, their expression and functions in cancer are largely unknown. In this study, we examined expression of NELL1 and NELL2 in renal cell carcinoma (RCC) using clinical specimens and cell lines. We show that, whereas NELL1 and NELL2 proteins are strongly expressed in renal tubules in non-cancerous areas of RCC specimens, their expression is significantly downregulated in cancerous areas. Silencing of NELL1 and NELL2 mRNA expression was also detected in RCC cell lines. Analysis of NELL1/2 promoter methylation status indicated that the CpG islands in the NELL1 and NELL2 genes are hypermethylated in RCC cell lines. NELL1 and NELL2 bind to RCC cells, suggesting that these cells express a receptor for NELL1 and NELL2 that can transduce signals. Furthermore, we found that both NELL1 and NELL2 inhibit RCC cell migration, and NELL1 further inhibits RCC cell adhesion. These results suggest that silencing of NELL gene expression by promoter hypermethylation plays roles in RCC progression by affecting cancer cell behavior.

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confidence: 99%

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Expression and regulatory effects on cancer cell behavior of NELL1 and NELL2 in human renal cell carcinoma

et al. 2015

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“…Therefore it seems unlikely that Robo receptors are responsible for the Nell2-medicated eye-specific retinogeniculate projection. In addition, whereas EGF-like repeats of the Nell2 protein appear to be responsible for repulsion of spinal commissural axons (Jaworski et al, 2015), our previous studies have revealed that cysteinerich domains exert inhibition of retinal axons (Nakamoto et al, 2014). These findings suggest that Nell2 regulates behaviour of retinal and spinal commissural axons through its different domains binding to distinct cognate receptors.…”

Section: Discussionmentioning

confidence: 90%

“…It has been previously reported that Nell2 is expressed in developing RGCs (Nakamoto et al, 2014;Nelson et al, 2002;Wang et al, 2007). It is possible that Nell2 is expressed specifically in contra-or ipsi-laterally projecting RGCs and is involved in specification of their laterality of projection.…”

Section: Nell Null Mice Show No Obvious Defects In Rgc Axon Pathfindingmentioning

confidence: 98%

“…To determine whether Nell2 is involved in development of the eye-specific projection, we examined the retinogeniculate projection in Nell2 -/mice (Matsuyama et al, 2004;Nakamoto et al, 2014). Overall structure and cytoarchitecture of the visual system (retina, optic chiasm, and dLGN) are maintained in the mutant mice ( Figs.…”

Section: Nell Null Mice Have Defects In the Eye-specific Retinogenicumentioning

confidence: 99%

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Nell2 regulates the contralateral-versus-ipsilateral visual projection as a layer-specific positional cue

Nakamoto

Durward

Horie

et al. 2018

Preprint

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In mammals with binocular vision, retinal ganglion cell (RGC) axons from each eye project to eye-specific layers in the contralateral and ipsilateral dorsal lateral geniculate nucleus (dLGN). Although layer-specific axon guidance cues that discriminate contralateral and ipsilateral RGC axons have long been postulated as a key mechanism for development of the eye-specific retinogeniculate projection, the molecular nature of such cues has remained elusive. Here we show that the extracellular glycoprotein Nell2 (also known as Nel) is expressed in the dorsomedial region of the dLGN, which corresponds to the layer receiving ipsilateral RGC axons. In Nell2 mutant mice, contralateral RGC axons invaded the ipsilateral layer of the dLGN, and ipsilateral axons terminated in partially fragmented patches, forming a mosaic pattern of contralateral and ipsilateral axon termination zones. In vitro, Nell2 exerted inhibitory effects on contralateral, but not ipsilateral, RGC axons. These results provide evidence that Nell2 acts as a layer-specific positional label in the dLGN that discriminates contralateral and ipsilateral RGC axons, and that it plays essential roles in establishment of the eye-specific projection patterns in the retinogeniculate system.

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Transposon-Mediated Stable Suppression of Gene Expression in the Developing Chick Retina

Nakamoto

2019

Retinal Development

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The embryonic chick has long been a favorite model system for in vivo studies of vertebrate development. However, a major technical limitation of the chick embryo has been the lack of efficient loss-of-function approaches for analyses of gene functions. Here, we describe a methodology in which a transgene encoding artificial microRNA sequences is introduced into embryonic chick retinal cells by in ovo electroporation and integrated into the genome using the Tol2 transposon system. We show that this methodology can induce potent and stable suppression of gene expression. This technique therefore provides a rapid and robust lossof-function approach for studies of gene function in the developing retina.

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Nel positively regulates the genesis of retinal ganglion cells by promoting their differentiation and survival during development

Cited by 6 publications

References 59 publications

Expression and regulatory effects on cancer cell behavior of NELL1 and NELL2 in human renal cell carcinoma

Expression and regulatory effects on cancer cell behavior of NELL1 and NELL2 in human renal cell carcinoma

Nell2 regulates the contralateral-versus-ipsilateral visual projection as a layer-specific positional cue

Transposon-Mediated Stable Suppression of Gene Expression in the Developing Chick Retina

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