The Molecular Mechanism of NELL2 Movement and Secretion in Hippocampal Progenitor HiB5 Cells

Ha, Chang Man; Hwang, Eun Mi; Kim, Eunju; Lee, Da Yong; Chang, Sunghoe; Lee, Byung Ju; Hong, Seong Geun; Park, Jae Yong

doi:10.1007/s10059-013-0216-5

Cited by 5 publications

(7 citation statements)

References 25 publications

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“…Secreting proteins visit the ER during the conventional release process. We previously designed a reporter vector to visualize intracellular localization of NELL2 (NELL2-EGFP) and observed that NELL2 travels through the ER and Golgi apparatus ( Ha et al, 2013 ). This result suggests that NELL2 follows the conventional release pathway.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Regulatory Role of NELL2 in Preproenkephalin Gene Expression

Kim

Lee

et al. 2022

Molecules and Cells

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Preproenkephalin (PPE) is a precursor molecule for multiple endogenous opioid peptides Leu-enkephalin (ENK) and Met-ENK, which are involved in a wide variety of modulatory functions in the nervous system. Despite the functional importance of ENK in the brain, the effect of brain-derived factor(s) on PPE expression is unknown. We report the dual effect of neural epidermal growth factor (EGF)-likelike 2 (NELL2) on PPE gene expression. In cultured NIH3T3 cells, transfection of NELL2 expression vectors induced an inhibition of PPE transcription intracellularly, in parallel with downregulation of protein kinase C signaling pathways and extracellular signal-regulated kinase. Interestingly, these phenomena were reversed when synthetic NELL2 was administered extracellularly. The in vivo disruption of NELL2 synthesis resulted in an increase in PPE mRNA level in the rat brain, suggesting that the inhibitory action of intracellular NELL2 predominates the activation effect of extracellular NELL2 on PPE gene expression in the brain. Biochemical and molecular studies with mutant NELL2 structures further demonstrated the critical role of EGF-like repeat domains in NELL2 for regulation of PPE transcription. These are the first results to reveal the spatio-specific role of NELL2 in the homeostatic regulation of PPE gene expression.

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Section: Discussionmentioning

confidence: 99%

Transcriptional Regulatory Role of NELL2 in Preproenkephalin Gene Expression

Kim

Lee

et al. 2022

Molecules and Cells

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“…Secreting proteins visit the ER during the conventional release process. We previously designed a reporter vector to visualize intracellular localization of NELL2 (NELL2-EGFP) and observed that NELL2 travels through the ER and Golgi apparatus [45]. This result suggests that NELL2 follows the conventional release pathway.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Regulatory Role of NELL2 in Preproenkephalin Gene Expression

Kim¹,

Kim²,

Ha³

et al. 2021

Preprint

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Preproenkephalin (PPE) is a precursor molecule for multiple endogenous opioid peptides Leu-enkephalin (ENK) and Met-ENK, which are involved in a wide variety of modulatory functions in the nervous system. Despite the functional importance of ENK in the brain, the effect of brain-derived factor(s) on PPE expression is unknown. We report the dual effect of neural epidermal growth factor (EGF)-like-like 2 (NELL2) on PPE gene expression. In cultured NIH3T3 cells, transfection of NELL2 expression vectors induced an inhibition of PPE transcription intracellularly, in parallel with downregulation of protein kinase C signaling pathways and extracellular signal-regulated kinase. Interestingly, these phenomena were reversed when synthetic NELL2 was administered extracellularly. The in vivo disruption of NELL2 synthesis resulted in an increase in PPE mRNA level in the rat brain, suggesting that the inhibitory action of intracellular NELL2 predominates the activation effect of extracellular NELL2 on PPE gene expression in the brain. Biochemical and molecular studies with mutant NELL2 structures further demonstrated the critical role of EGF-like repeat domains in NELL2 for regulation of PPE transcription. These are the first results to reveal the spatio-specific role of NELL2 in the homeostatic regulation of PPE gene expression.

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“…Independent studies have also revealed that NELL2 signaling is necessary for normal onset of female puberty and cyclicity [13]. Taken together, our group has demonstrated a versatile role for NELL2 in postnatal brain development through modification of neuronal function and fate, including vesicle transport and release, neuronal protection, survival and aggregation [14][15][16][17][18][19].…”

Section: Commentarymentioning

confidence: 96%

Versatile role of NELL2 in brain

Kim¹,

Jeong²

2018

J Cell Signal

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CommentaryA precise communication between the central nervous system (CNS) and the periphery is fundamental in achieving a fine balance between energy intake and expenditure. When this crosstalk is impaired, obesity, a metabolic state characterized by excess fat accumulation in peripheral tissues, occurs. Obesity is the foundation for several metabolic syndromes, such as type 2 diabetes, stroke, and hypertension, all of which are leading causes of mortality. It is no doubt that multiple regions of the brain participate in the regulation of energy homeostasis. However, the hypothalamus has long been highlighted in metabolism regulation as it forms a coherent whole for direct detection of circulating metabolic signals, integration of metabolic information obtained from periphery and other CNS regions, and production of adequate molecular and behavioral outcomes that preserve whole body energy homeostasis [1][2][3][4].NELL2, a mammalian neural tissue-enriched EGF-Like Like protein 2, is a newly identified secreting molecule from neurons as a neurotransmitter [5,6]. Although NELL2 is broadly distributed throughout the mammalian brain, we previously reported that its expression is brain region-specific and cell type-dependent [5]. Importantly, NELL2 is produced relatively high in the hypothalamus compared to other brain regions [5,7]. In addition, core hypothalamic nuclei known to play a critical role in metabolism regulation, such as the paraventricular nucleus, ventromedial nucleus, and the arcuate nucleus of the hypothalamus (ARC) are also a main site of NELL2 production [5,7]. This anatomical observation allowed us to hypothesize a potential function of NELL2 in whole body metabolism regulation.Recently, we reported "A Role of Central NELL2 in the Regulation of Feeding Behavior in Rats" [7]. In this work, we demonstrated a role for central NELL2 in rodent feeding behavior and energy homeostasis, using an antisense oligonucleotide-dependent gene blocking system for an acute ablation of NELL2 biosynthesis in adult rodent brain in vivo. Importantly, adult rats with acute hypothalamic NELL2 ablation showed a significant reduction in body weight gain under ad libitum, normal chow feeding conditions when compared to controls. This response was attributed to a reduction in food intake behavior. On the other hand, blockade of NELL2 in the hypothalamus did not affect animal's water intake, nor produced sickness behavior. These behavioral studies have demonstrated a role of hypothalamic NELL2 signaling in feeding behavior. Interestingly, short-term food intake followed by overnight fasting was not differ between experimental and control groups, suggesting that NELL2 signaling in the hypothalamus is specific for ad libitum appetite behavior. We also observed in this study that mRNA level of NELL2 expression in the hypothalamus was elevated during fasting, when compared to a fed state. Therefore, it is likely that central NELL2 is responsible for an orexigenic mechanism in rodents.Anatomical verification revealed that NELL2 i...

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The Molecular Mechanism of NELL2 Movement and Secretion in Hippocampal Progenitor HiB5 Cells

Cited by 5 publications

References 25 publications

Transcriptional Regulatory Role of NELL2 in Preproenkephalin Gene Expression

Transcriptional Regulatory Role of NELL2 in Preproenkephalin Gene Expression

Transcriptional Regulatory Role of NELL2 in Preproenkephalin Gene Expression

Versatile role of NELL2 in brain

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