The Insulin-Like Growth Factor (IGF) Receptor Type 1 (IGF1R) as an Essential Component of the Signalling Network Regulating Neurogenesis

Annenkov, Alexander

doi:10.1007/s12035-009-8081-0

Cited by 63 publications

(42 citation statements)

References 276 publications

(221 reference statements)

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“…Because NSPCs have the potential to differentiate into mature functional neurons before transplantation [16], these cells could generate neurons without extrinsic astrogenic direction in chronically injured spinal cords. In addition, FGF-2 and IGF-1, essential regulators of neurogenesis [35,36,46], were constantly upregulated during the chronic phase of SCI. These neurogenic factors may support the neurogenesis of engrafted cells.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Activities of Engrafted Neural Stem/Precursor Cells Are Not Dormant in the Chronically Injured Spinal Cord

et al. 2013

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The transplantation of neural stem/precursor cells (NSPCs) is a promising therapeutic strategy for many neurodegenerative disorders including spinal cord injury (SCI) because it provides for neural replacement or trophic support. This strategy is now being extended to the treatment of chronic SCI patients. However, understanding of biological properties of chronically transplanted NSPCs and their surrounding environments is limited. Here, we performed temporal analysis of injured spinal cords and demonstrated their multiphasic cellular and molecular responses. In particular, chronically injured spinal cords were growth factorenriched environments, whereas acutely injured spinal cords were enriched by neurotrophic and inflammatory factors. To determine how these environmental differences affect engrafted cells, NSPCs transplanted into acutely, subacutely, and chronically injured spinal cords were selectively isolated by flow cytometry, and their whole transcriptomes were compared by RNA sequencing. This analysis revealed that NSPCs produced many regenerative/ neurotrophic molecules irrespective of transplantation timing, and these activities were prominent in chronically transplanted NSPCs. Furthermore, chronically injured spinal cords permitted engrafted NSPCs to differentiate into neurons/oligodendrocytes and provided more neurogenic environment for NSPCs than other environments. Despite these results demonstrate that transplanted NSPCs have adequate capacity in generating neurons/oligodendrocytes and producing therapeutic molecules in chronic SCI microenvironments, they did not improve locomotor function. Our results indicate that failure in chronic transplantation is not due to the lack of therapeutic activities of engrafted NSPCs but the refractory state of chronically injured spinal cords. Environmental modulation, rather modification of transplanting cells, will be significant for successful translation of stem cell-based therapies into chronic SCI patients.

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Section: Discussionmentioning

confidence: 99%

Therapeutic Activities of Engrafted Neural Stem/Precursor Cells Are Not Dormant in the Chronically Injured Spinal Cord

et al. 2013

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“…The IGF signaling pathway has been shown to activate two major signaling cascades, the PI3K/Akt pathway and the MEK/Erk pathway (Annenkov, 2009). To determine which pathway is activated by IGF1R during cochlear development, we examined changes in the phosphorylation levels of Akt, a direct downstream target of PI3K, and Erk, a direct downstream target of MEK, in serum-starved cochlear cultures treated with 1 g/ml IGF1 for 20 min.…”

Section: Pi3 Kinase Is a Downstream Target Of Igf1r In The Developingmentioning

confidence: 99%

Insulin-Like Growth Factor Signaling Regulates the Timing of Sensory Cell Differentiation in the Mouse Cochlea

Okano¹,

Xuan²,

Kelley³

2011

J. Neurosci.

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The mammalian auditory sensory epithelium, the organ of Corti, is a highly ordered cellular structure that comprises two types of auditory hair cells and several types of nonsensory supporting cells. During embryogenesis, a stereotyped sequence of cellular and molecular events is required for its development. These processes are assumed to be regulated by multiple growth and transcription factors. However, the majority of these factors have not been identified. One potential regulator of cochlear development is the insulinlike growth factor (IGF) signaling family. To examine the roles of the IGF pathway in inner ear formation, cochleae from Igf1r mutant mice were analyzed. Deletion of Igf1r leads to several changes in inner ear development including a shortened cochlear duct, a decrease in the total number of cochlear hair cells, and defects in the formation of the semicircular canals. In addition, maturation of the cochlear sensory epithelium was delayed at the transition point between cellular proliferation and differentiation. To determine the molecular basis for these defects, inhibition of IGF signaling was replicated pharmacologically in vitro. Results indicated that IGF signaling regulates cochlear length and hair cell number as well as Atoh1 expression through the phosphatidylinositol 3-kinase/Akt signaling pathway. These results demonstrate novel roles for IGF signaling in inner ear development including regulation of vestibular formation, length of the cochlear duct, and the number of cochlear hair cells. The results also provide new insights regarding the pathological processes that underlie auditory defects in the absence of IGF signaling in both humans and mice.

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“…The biologic actions of IGF-1 are mediated by the IGF-1 receptor, a member of the receptor tyrosine kinase family that induces dimerization and activates several downstream pathways to transmit proliferative signals after extracellular stimulations (Chitnis et al, 2008;Annenkov 2009;Bibollet-Bahena and Almazan 2009). Our results show that ABG-001 induces IGF-1 receptor phosphorylation and that AG1024, T9576, and IGF-1 receptor siRNA inhibit PC12 cell differentiation induced by ABG-001 (Figs.…”

Section: Discussionmentioning

confidence: 99%

Neuritogenic Activity of Tetradecyl 2,3-Dihydroxybenzoate Is Mediated through the Insulin-Like Growth Factor 1 Receptor/Phosphatidylinositol 3 Kinase/Mitogen-Activated Protein Kinase Signaling Pathway

Tang¹,

Gao²,

Kawatani³

et al. 2015

Molecular Pharmacology

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Tetradecyl 2,3-dihydroxybenzoate (ABG-001) is a lead compound derived from neuritogenic gentisides. In the present study, we investigated the mechanism by which ABG-001 induces neurite outgrowth in a rat adrenal pheochromocytoma cell line (PC12). Inhibitors of insulin-like growth factor 1 (IGF-1) receptor, phosphatidylinositol 3-kinase (PI3K), and extracellular signal-regulated kinase (ERK) 1/2 significantly decreased ABG-001-induced neurite outgrowth. Western blot analysis revealed that ABG-001 significantly induced phosphorylation of IGF-1 receptor, protein kinase B (Akt), ERK, and cAMP responsive element-binding protein (CREB). These effects were markedly reduced by addition of the corresponding inhibitors. We also found that ABG-001-induced neurite outgrowth was reduced by protein kinase C inhibitor as well as small-interfering RNA against the IGF-1 receptor. Furthermore, like ABG-001, IGF-1 also induced neurite outgrowth of PC12 cells, and low-dose nerve growth factor augmented the observed effects of ABG-001 on neurite outgrowth. These results suggest that ABG-001 targets the IGF-1 receptor and activates PI3K, mitogen-activated protein kinase, and their downstream signaling cascades to induce neurite outgrowth.

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The Insulin-Like Growth Factor (IGF) Receptor Type 1 (IGF1R) as an Essential Component of the Signalling Network Regulating Neurogenesis

Cited by 63 publications

References 276 publications

Therapeutic Activities of Engrafted Neural Stem/Precursor Cells Are Not Dormant in the Chronically Injured Spinal Cord

Therapeutic Activities of Engrafted Neural Stem/Precursor Cells Are Not Dormant in the Chronically Injured Spinal Cord

Insulin-Like Growth Factor Signaling Regulates the Timing of Sensory Cell Differentiation in the Mouse Cochlea

Neuritogenic Activity of Tetradecyl 2,3-Dihydroxybenzoate Is Mediated through the Insulin-Like Growth Factor 1 Receptor/Phosphatidylinositol 3 Kinase/Mitogen-Activated Protein Kinase Signaling Pathway

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