Functional Characterization of the Dendritically Localized mRNA Neuronatin in Hippocampal Neurons

Oyang, Elaine L.; Davidson, Bonnie C.; Lee, Winfong; Poon, Michael M.

doi:10.1371/journal.pone.0024879

Cited by 52 publications

(53 citation statements)

References 81 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is interesting that NNAT was not detected in dendrites of other retinal neurons, as it has been observed in hippocampal neurons (Oyang et al, 2011). The only exception of altered NNAT intracellular localization was detected in RHO knockout retinas at P15.…”

Section: Resultsmentioning

confidence: 67%

Neuronatin is a stress-responsive protein of rod photoreceptors

et al. 2016

View full text Add to dashboard Cite

Neuronatin (NNAT) is a small transmembrane proteolipid that is highly expressed in the embryonic developing brain and several other peripheral tissues. This study is the first to provide evidence that NNAT is detected in the adult retina of various adult rod-dominant mammals, including wild-type (WT) rodents, transgenic rodents expressing mutant S334ter, P23H, or T17M rhodopsin, non-human primates, humans, and cone-dominant tree shrews. Immunohistochemical and quantitative real time polymerase chain reaction (qRT-PCR) analyses were applied to detect NNAT. Confocal microscopy analysis revealed that NNAT immunofluorescence is restricted to the outer segments (OSs) of photoreceptors without evidence of staining in other retinal cell types across all mammalian species. Moreover, in tree shrew retinas, we found NNAT to be co-localized with rhodopsin, indicating its predominant expression in rods. The rod-derived expression of NNAT was further confirmed by qRT-PCR in isolated rod photoreceptor cells. We also used these cells to mimic cellular stress in transgenic retinas by treating them with the endoplasmic reticulum stress inducer, tunicamycin. Thus, our data revealed accumulation of NNAT around the nucleus as compared to dispersed localization of NNAT within control cells. This distribution coincided with the partial intracellular mislocalization of NNAT to the outer nuclear layer observed in transgenic retinas. In addition, stressed retinas demonstrated an increase of NNAT mRNA and protein levels. Therefore, our study demonstrated that NNAT is a novel stress-responsive protein with a potential structural and/or functional role in adult mammalian retinas.

show abstract

Section: Resultsmentioning

confidence: 67%

Neuronatin is a stress-responsive protein of rod photoreceptors

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Accordingly, it has been recently reported that Nnat mRNA is translated in hippocampal dendrites in response to blockade of action potentials and NMDA-receptor-dependent synaptic transmission and can adjust dendritic calcium levels by regulating intracellular calcium storage. 34 Authors thus proposed that neuronatin may impact synaptic plasticity by modulating dendritic calcium levels, thereby potentially regulating neuronal excitability, receptor trafficking and calcium-dependent signaling. In adult brain, Nnat is predominantly expressed in parvalbumin-positive GABAergic interneurons.…”

Section: Discussionmentioning

confidence: 99%

Altered expression of neuropeptides in FoxG1-null heterozygous mutant mice

et al. 2015

View full text Add to dashboard Cite

Foxg1 gene encodes for a transcription factor essential for telencephalon development in the embryonic mammalian forebrain. Its complete absence is embryonic lethal while Foxg1 heterozygous mice are viable but display microcephaly, altered hippocampal neurogenesis and behavioral and cognitive deficiencies. In order to evaluate the effects of Foxg1 alteration in adult brain, we performed expression profiling in total brains from Foxg1+/ − heterozygous mutants and wild-type littermates. We identified statistically significant differences in expression levels for 466 transcripts (Po0.001), 29 of which showed a fold change ≥ 1.5. Among the differentially expressed genes was found a group of genes expressed in the basal ganglia and involved in the control of movements. A relevant (three to sevenfold changes) and statistically significant increase of expression, confirmed by qRT-PCR, was found in two highly correlated genes with expression restricted to the hypothalamus: Oxytocin (Oxt) and Arginine vasopressin (Avp). These neuropeptides have an important role in maternal and social behavior, and their alteration is associated with impaired social interaction and autistic behavior. In addition, Neuronatin (Nnat) levels appear significantly higher both in Foxg1+/ − whole brain and in hippocampal neurons after silencing Foxg1, strongly suggesting that it is directly or indirectly repressed by Foxg1. During fetal and neonatal brain development, Nnat may regulate neuronal excitability, receptor trafficking and calcium-dependent signaling and, in the adult brain, it is predominantly expressed in parvalbumin-positive GABAergic interneurons. Overall, these results implicate the overexpression of a group of neuropeptides in the basal ganglia, hypothalamus, cortex and hippocampus in the pathogenesis FOXG1 behavioral impairments.

show abstract

“…Neuronatin has also been proposed to mediate its effects through modulation of cellular calcium flux, with consequent effects on activation of downstream signaling pathways, including extracellular signal-regulated kinase (18, 24). It has been reported that overexpression of the α-isoform resulted in phosphorylation and therefore likely increased transcriptional activation by cAMP-response element-binding protein (CREB) in adipocytes (33).…”

Section: Discussionmentioning

confidence: 99%

“…Neuronatin mRNA can be spliced into two variants, generating proteins of 81 (α) and 54 (β) amino acids in length (4, 13). Both variants are predicted to possess a single transmembrane domain and seem to reside in the endoplasmic reticulum (ER) in neurons (12, 18, 24). Neuronatin-α is the isoform preferentially reduced in the β-cells of diabetic rodents (1, 12).…”

mentioning

confidence: 99%

Loss of neuronatin promotes “browning” of primary mouse adipocytes while reducing Glut1-mediated glucose disposal

Gburcik

Cleasby

Timmons

2013

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

Failure of white adipose tissue to appropriately store excess metabolic substrate seems to underpin obesity-associated type 2 diabetes. Encouraging “browning” of white adipose has been suggested as a therapeutic strategy to help dispose of excess stored lipid and ameliorate the resulting insulin resistance. Genetic variation at the DNA locus encoding the novel proteolipid neuronatin has been associated with obesity, and we recently observed that neuronatin expression is reduced in subcutaneous adipose tissue from obese humans. Thus, to explore the function of neuronatin further, we used RNAi to silence its expression in murine primary adipocyte cultures and examined the effects on adipocyte phenotype. We found that primary adipocytes express only the longer isoform of neuronatin. Loss of neuronatin led to increased mitochondrial biogenesis, indicated by greater intensity of MitoTracker Green staining. This was accompanied by increased expression of UCP1 and the key genes in mitochondrial oxidative phosphorylation, PGC-1α, Cox8b, and Cox4 in primary subcutaneous white adipocytes, indicative of a “browning” effect. In addition, phosphorylation of AMPK and ACC was increased, suggestive of increased fatty acid utilization. Similar, but less pronounced, effects of neuronatin silencing were also noted in primary brown adipocytes. In contrast, loss of neuronatin caused a reduction in both basal and insulin-stimulated glucose uptake and glycogen synthesis, likely mediated by a reduction in Glut1 protein upon silencing of neuronatin. In contrast, loss of neuronatin had no effect on insulin signaling. In conclusion, neuronatin appears to be a novel regulator of browning and metabolic substrate disposal in white adipocytes.

show abstract

Functional Characterization of the Dendritically Localized mRNA Neuronatin in Hippocampal Neurons

Cited by 52 publications

References 81 publications

Neuronatin is a stress-responsive protein of rod photoreceptors

Neuronatin is a stress-responsive protein of rod photoreceptors

Altered expression of neuropeptides in FoxG1-null heterozygous mutant mice

Loss of neuronatin promotes “browning” of primary mouse adipocytes while reducing Glut1-mediated glucose disposal

Contact Info

Product

Resources

About