Induction of cell growth by insulin and insulin-like growth factor-I is associated with jun expression in the otic vesicle

León, Yolanda; Sanz, Carmen; Giráldez, Fernando; Varela-Nieto, Isabel

doi:10.1002/(sici)1096-9861(19980831)398:3<323::aid-cne2>3.0.co;2-1

Cited by 32 publications

(30 citation statements)

References 54 publications

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“…Human and chicken IGF-I are very similar in their ability to stimulate growth of the otic vesicle. By contrast, the potency of chicken and bovine insulin are very differentthe former being comparable to IGF-I and the later ineffective [26].…”

Section: Functions and Role Of Igf-l In Otic Developmentmentioning

confidence: 90%

“…GPI serves as precursor for soluble IPG molecules that display biological activity (reviewed by Varela-Nieto et al [53]) [49,22]. Furthermore, IPG analogues with biological activity have also been synthesized 135,56], as is the case with the synthetic disaccharide C3, that shows a powerful mitogenic activity in the otic vesicle [56,26].…”

Section: Signaling By Igf-lmentioning

confidence: 99%

“…Evidence from different experimental approaches suggests that IPG is released to the extracellular media to be then taken up by target cells 139, 53,41,26]. The hydrolysis of GPI by specific phospholipases and the consequent generation of IPG is receptor-operated and part of the mechanism of action of several hormones, cytokines and growth factors [13,21,22].…”

Section: Signaling By Igf-lmentioning

confidence: 99%

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Involvement of Insulin-Like Growth Factor-I in Inner Ear Organogenesis and Regeneration

León

Sanz²,

Frago³

et al. 1999

Horm Metab Res

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The verterbrate inner ear is an excellent model system to study signalling mechanisms in embryonic development. During the last years, insulin-like growth factor-I (IGF-l) has attracted attention in relation to the regulation of inner ear ontogenesis. IGF-I and its high-affinity tyrosine-kinase receptor are expressed during early stages of inner ear development. IGF-l is a powerful mitogen for the otic vesicle, where it stimulates cell-division and mitogenic signalling cascades. Later in development, IGF-l also promotes survival and neurogenesis of the otic neurones in the cochleovestibular ganglion (CVG). The actions of IGF-l are associated with the generation of lipidic messengers and the activation of Raf kinase, which results in the rapid induction of the expression of the proliferative cell nuclear antigen (PCNA) and the nuclear proto-oncogenes c-fos and c-Jun. Regulation of organogenesis involves a dynamic balance of the mechanisms regulating cell division, differentiation and death. A model is proposed where this balance is the consequence of the action of IGF-l and NGF, which converge in Raf activation or suppression. The combinatorial expression of Jun and Fos family members in particular domains of the otic vesicle would be the final result of such cascade. Some of these mechanisms may be also implicated in otic regeneration.

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Section: Functions and Role Of Igf-l In Otic Developmentmentioning

confidence: 90%

Section: Signaling By Igf-lmentioning

confidence: 99%

Section: Signaling By Igf-lmentioning

confidence: 99%

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Involvement of Insulin-Like Growth Factor-I in Inner Ear Organogenesis and Regeneration

León

Sanz²,

Frago³

et al. 1999

Horm Metab Res

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“…Otic vesicles were dissected from stage HH18 embryos (65 h of incubation), transferred into four-well culture-plates (Nunc, Roskilde, Denmark) and incubated at 37°C in a water-saturated atmosphere containing 5% CO 2 as described previously [35]. The standard culture medium consisted of M199 medium with Earle's salts (Sigma-Aldrich, Saint Louis, MO) supplemented with 2 mM glutamine (Gibco, Paisley, UK) and antibiotics [50 IU/ml penicillin (Ern, Barcelona, Spain) and 50 mg/ml streptomycin (CEPA, Madrid, Spain)].…”

Section: Methodsmentioning

confidence: 99%

AKT Signaling Mediates IGF-I Survival Actions on Otic Neural Progenitors

et al. 2012

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BackgroundOtic neurons and sensory cells derive from common progenitors whose transition into mature cells requires the coordination of cell survival, proliferation and differentiation programmes. Neurotrophic support and survival of post-mitotic otic neurons have been intensively studied, but the bases underlying the regulation of programmed cell death in immature proliferative otic neuroblasts remains poorly understood. The protein kinase AKT acts as a node, playing a critical role in controlling cell survival and cell cycle progression. AKT is activated by trophic factors, including insulin-like growth factor I (IGF-I), through the generation of the lipidic second messenger phosphatidylinositol 3-phosphate by phosphatidylinositol 3-kinase (PI3K). Here we have investigated the role of IGF-dependent activation of the PI3K-AKT pathway in maintenance of otic neuroblasts.Methodology/Principal FindingsBy using a combination of organotypic cultures of chicken (Gallus gallus) otic vesicles and acoustic-vestibular ganglia, Western blotting, immunohistochemistry and in situ hybridization, we show that IGF-I-activation of AKT protects neural progenitors from programmed cell death. IGF-I maintains otic neuroblasts in an undifferentiated and proliferative state, which is characterised by the upregulation of the forkhead box M1 (FoxM1) transcription factor. By contrast, our results indicate that post-mitotic p27Kip-positive neurons become IGF-I independent as they extend their neuronal processes. Neurons gradually reduce their expression of the Igf1r, while they increase that of the neurotrophin receptor, TrkC.Conclusions/SignificanceProliferative otic neuroblasts are dependent on the activation of the PI3K-AKT pathway by IGF-I for survival during the otic neuronal progenitor phase of early inner ear development.

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“…These IGF1R-mediated effects were observed in the middle to late stage of cochlear development and were dependent on the PI3K/Akt pathway but not on the MEK/ERK pathway, as indicated by detection of phosphorylated downstream of IGF1R and by inhibitor experiments (Okano et al, 2011). In contrast, the growth and proliferative effects of IGF-1 on otocysts and its survival effects in proliferative otic neuroblasts during the early developmental stage were dependent on the MEK/ERK pathway (Leon et al, 1998; Sanz et al, 1999; Magarinos et al, 2010) and the PI3K/AKT pathway (Aburto et al, 2012), respectively. The effector molecules of IGF-1 in the late stage of cochlear development have been studied using comprehensive gene expression analysis; several transcriptional factors (FoxM1, Mef2a, and Mef2d) have been identified as effectors of IGF-1 signaling (Sanchez-Calderon et al, 2010).…”

Section: Igf-1 and The Inner Earmentioning

confidence: 96%

Application of insulin-like growth factor-1 in the treatment of inner ear disorders

2014

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Sensorineural hearing loss (SNHL) is considered an intractable disease, given that hair and supporting cells (HCs and SCs) of the postnatal mammalian cochlea are unable to regenerate. However, with progress in regenerative medicine in the 21st century, several innovative approaches for achieving regeneration of inner ear HCs and SCs have become available. These methods include stem cell transplantation, overexpression of specific genes, and treatment with growth factors. Insulin-like growth factor-1 (IGF-1) is one of the growth factors that are involved in the development of the inner ear. Treatment with IGF-1 maintains HC numbers in the postnatal mammalian cochlea after various types of HC injuries, with activation of two major pathways downstream of IGF-1 signaling. In the aminoglycoside-treated neonatal mouse cochlear explant culture, promotion of the cell-cycle in SCs as well as inhibition of HC apoptosis was observed in the IGF-1-treated group. Activation of downstream molecules was observed in SCs and, in turn, SCs contribute to the maintenance of HC numbers. Using comprehensive analysis of the gene expression, the candidate effector molecules of the IGF-1 signaling pathway in the protection of HCs were identified as Netrin1 and Gap43. Based on these studies, a clinical trial has sought to investigate the effects of IGF-1 on SNHL. Sudden SNHL (SSHL) that was refractory to systemic steroids was treated with IGF-1 in a gelatin hydrogel and the outcome was compared with a historical control of hyperbaric oxygen therapy. The proportion of patients showing hearing improvement was significantly higher in the IGF-1-treatment group at 24 weeks after treatment than in the control group. A randomized clinical trial is ongoing to compare the effect of IGF-1 treatment with that of intra-tympanic steroids for SSHL that is refractory to systemic steroids.

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Induction of cell growth by insulin and insulin-like growth factor-I is associated with jun expression in the otic vesicle

Cited by 32 publications

References 54 publications

Involvement of Insulin-Like Growth Factor-I in Inner Ear Organogenesis and Regeneration

Involvement of Insulin-Like Growth Factor-I in Inner Ear Organogenesis and Regeneration

AKT Signaling Mediates IGF-I Survival Actions on Otic Neural Progenitors

Application of insulin-like growth factor-1 in the treatment of inner ear disorders

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