OTX2 regulates the expression of TAp63 leading to macular and cochlear neuroepithelium development

Palombo, Ramona; Porta, Giovanni; Bruno, Ernesto; Provero, Paolo; Serra, Valeria; Neduri, Karthik; Viziano, Andrea; Alessandrini, Marco; Micarelli, Alessandro; Ottaviani, Fabrizio; Melino, Gerry; Terrinoni, Alessandro

doi:10.18632/aging.100839

Cited by 7 publications

(11 citation statements)

References 27 publications

(38 reference statements)

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“…6b). Some of the TF genes that are highly expressed in neonatal SCs have been reported to play roles in promoting HC fate and patterning regulation during inner ear development, including Rfx1 [80], Tbx18 [81], Otx2 [82, 83], Dlx2 [84], and Mycn [85]. We also performed qPCR to confirm the RNA-seq data, and the results were consistent with the RNA-seq analysis data (Fig.…”

Section: Resultssupporting

confidence: 74%

“…And it plays a role in brain, craniofacial, and sensory organ development [109, 110]. In the inner ear, Otx2 can induce Hes5 and lead to the differentiation of both cochlear and macular neuroepithelium [82, 83]. In the chick inner ear, the expression of Dlx1 and Dlx2 during the later stages of inner ear morphogenesis is limited to cochlear and vestibular nerves, and expression levels are lower than in the early stages of morphogenesis [84].…”

Section: Discussionmentioning

confidence: 99%

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Age-related transcriptome changes in Sox2+ supporting cells in the mouse cochlea

et al. 2019

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BackgroundInner ear supporting cells (SCs) in the neonatal mouse cochlea are a potential source for hair cell (HC) regeneration, but several studies have shown that the regeneration ability of SCs decreases dramatically as mice age and that lost HCs cannot be regenerated in adult mice. To better understand how SCs might be better used to regenerate HCs, it is important to understand how the gene expression profile changes in SCs at different ages.MethodsHere, we used Sox2GFP/+ mice to isolate the Sox2+ SCs at postnatal day (P)3, P7, P14, and P30 via flow cytometry. Next, we used RNA-seq to determine the transcriptome expression profiles of P3, P7, P14, and P30 SCs. To further analyze the relationships between these age-related and differentially expressed genes in Sox2+ SCs, we performed gene ontology (GO) analysis.ResultsConsistent with previous reports, we also found that the proliferation and HC regeneration ability of isolated Sox2+ SCs significantly decreased as mice aged. We identified numerous genes that are enriched and differentially expressed in Sox2+ SCs at four different postnatal ages, including cell cycle genes, signaling pathway genes, and transcription factors that might be involved in regulating the proliferation and HC differentiation ability of SCs. We thus present a set of genes that might regulate the proliferation and HC regeneration ability of SCs, and these might serve as potential new therapeutic targets for HC regeneration.ConclusionsIn our research, we found several genes that might play an important role in regulating the proliferation and HC regeneration ability of SCs. These datasets are expected to serve as a resource to provide potential new therapeutic targets for regulating the ability of SCs to regenerate HCs in postnatal mammals.

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Section: Resultssupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Age-related transcriptome changes in Sox2+ supporting cells in the mouse cochlea

et al. 2019

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“…OTX2 can transactivate TAp63, via a responsive element located into the intron 1 of the gene, whereas there is not a transcriptional regulation of ∆Np63. These results can identify a regulatory cascade going from OTX2 to TAp63, arriving to the Notch pathway [40].…”

Section: Introductionmentioning

confidence: 90%

Role of p63 isoform balance in recurrent nasal polyps

Terrinoni¹,

Palombo²,

Pitolli³

et al. 2018

Otorhinolaryngol Head Neck Sur

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Objective: Nasal polyps are, benign growths outgrowths of sinonasal tissue, affecting approximately 1-4% of the population. They have been correlated to the presence of chronic inflammation, but the molecular underlying mechanisms has not been completely defined. Defective epithelial barrier has been correlated with chronic rhinosinusitis (CRS) and nasal polyps (NPs) Moreover, a variation of ΔNp63 isoform expression has been noted in human airway epithelial cells and in the NPs epithelium. The benign lesion in some patients can have a recurrence, and the difference between recurrent and not recurrent patients is still unclear.The aim of the study was to molecularly characterise NPs patients, distinguishing between patients presenting NP recurrence after surgical treatment respect to those in which recurrence has been not reported. Methods:In the present work we analysed a cohort of patients affected by nasal polyposis, all submitted to Functional Endoscopic Sinus Surgery (FESS). The patients have been six-monthly clinical, checked in the two years following surgery. In all patients we analysed keratin 5, and p63 isoform expression, by RTqPCR using fresh NPs tissues taken after surgery. Moreover, confocal imunnofluorescence analysis again for p63 and Keratin 5 has been performed on fixed sections. Results and conclusion:The results show high ΔNp63 expression and keratin 5, in nasal polyps of patients. The analysis of the expression level of the TAp63 isoform, shows a differential expression between patients with recurrence, respect to the not recurring. A more comprehensive marker could be considered the ΔN/TAp63 ratio. In fact, even though ΔNp63 is expressed in non-recurrent patients the ratio ΔN/TAp63 result significantly lower in these patients. This clearly indicates that the status of TA63 expression, and represented by ΔN/TAp63 ratio, could be considered a prognostic markers of low recurrence probability. Since TAp63 is also upregulated by HDAC inhibitors could be the consideration of local treatment of nasal polyps with these molecules.

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“…The ATP level was measured based on a luciferin–luciferase reaction, using the ADP/ATP Ratio Assay Kit (Abcam, Cambridge, UK,), following the manufacturer’s instructions. See also [49] for more information on this.…”

Section: Methodsmentioning

confidence: 99%

Luteolin-7-O-β-d-Glucoside Inhibits Cellular Energy Production Interacting with HEK2 in Keratinocytes

Palombo

Caporali

Falconi

et al. 2019

IJMS

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Flavonoids have been demonstrated to affect the activity of many mammalian enzyme systems. Their functional phenolic groups are able to mediate antioxidant effects by scavenging free radicals. Molecules of this class have been found able to modulate the activity of kinases, phospholipase A2, cyclooxygenases, lipoxygenase, glutathione S-transferase, and many others. Recently, it has been demonstrated that luteolin, in the form of Luteolin-7-O-β-d-glucoside (LUT-7G) is able to induce the keratinocyte differentiation process in vitro. This flavonoid is able to counteract the proliferative effects of IL-22/IL6 pathway by the inhibition of STAT3 activity also in vivo in a psoriatic mouse model. Observations on energy metabolism changes of differentiating cells led us to perform a complete metabolomics analysis using human primary keratinocytes treated with LUT-7G. Our results show that LUT-7G, is not only able to impair the nuclear translocation of STAT3, but it also blocks the energy metabolism pathway, depressing the glycolytic and Krebs pathway by the inhibition of hexokinase 2 activity. These data confirm that LUT-7G can be proposed as a potential candidate for the treatment of inflammatory and proliferative diseases, but its role as a hexokinase 2 (HEK2) inhibitor opens new perspectives in nutritional science, and especially in cancer therapy, in which the inhibition of the Warburg effect could be relevant.

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OTX2 regulates the expression of TAp63 leading to macular and cochlear neuroepithelium development

Cited by 7 publications

References 27 publications

Age-related transcriptome changes in Sox2+ supporting cells in the mouse cochlea

Age-related transcriptome changes in Sox2+ supporting cells in the mouse cochlea

Role of p63 isoform balance in recurrent nasal polyps

Luteolin-7-O-β-d-Glucoside Inhibits Cellular Energy Production Interacting with HEK2 in Keratinocytes

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