The Neuregulin1/ErbB system is selectively regulated during peripheral nerve degeneration and regeneration

Ronchi, Giulia; Haastert‐Talini, Kirsten; Fornasari, Benedetta Elena; Perroteau, Isabelle; Geuna, Stefano; Gambarotta, Giovanna

doi:10.1111/ejn.12974

Cited by 43 publications

(59 citation statements)

References 48 publications

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“…Our previous analysis of uninjured nerves had revealed an increase in p-AKT in the cKO (Ma et al 2015), and at 1 d after injury, there was a similar increase in AKT phosphorylation at Thr308 and Ser473, which are catalyzed by PDK1 and mTORC2, respectively (Andjelković et al 1997; Sarbassov et al 2005) (Figure 2). At 1 d after injury, there is little change in p-AKT in wild type mice (Norrmén et al 2018; Ronchi et al 2016). …”

Section: Resultsmentioning

confidence: 99%

Polycomb repression regulates Schwann cell proliferation and axon regeneration after nerve injury

Duong

Moran

et al. 2018

Glia

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The transition of differentiated Schwann cells to support of nerve repair after injury is accompanied by remodeling of the Schwann cell epigenome. The EED-containing polycomb repressive complex 2 (PRC2) catalyzes histone H3K27 methylation and represses key nerve repair genes such as Shh, Gdnf and Bdnf, and their activation is accompanied by loss of H3K27 methylation. Analysis of nerve injury in mice with a Schwann cell-specific loss of EED showed the reversal of polycomb repression is required and a rate limiting step in the increased transcription of Neuregulin 1 (type I), which is required for efficient remyelination. However, mouse nerves with EED-deficient Schwann cells display slow axonal regeneration with significantly low expression of axon guidance genes, including Sema4f and Cntf. Finally, EED loss causes impaired Schwann cell proliferation after injury with significant induction of the Cdkn2a cell cycle inhibitor gene. Interestingly, PRC2 subunits and CDKN2A are commonly co-mutated in the transition from benign neurofibromas to malignant peripheral nerve sheath tumors (MPNST’s). RNA-seq analysis of EED-deficient mice identified PRC2-regulated molecular pathways that may contribute to the transition to malignancy in neurofibromatosis.

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Section: Resultsmentioning

confidence: 99%

Polycomb repression regulates Schwann cell proliferation and axon regeneration after nerve injury

Duong

Moran

et al. 2018

Glia

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“…Interestingly, it appeared that one of the dysregulated neuronal pathways was linked to neurotrophins, which are proteins that are known to be essential for differentiation and survival of peripheral neurons (Reichardt, 2006; Tourtellotte, 2016). Moreover, other essential pathways for accurate development of the nervous system seem to be altered in FD pathology, such as the axon guidance and ErbB signaling pathways, with the latter being remarkably associated with peripheral nervous system regeneration (Ronchi et al, 2015). …”

Section: Resultsmentioning

confidence: 99%

MicroRNA screening identifies a link between NOVA1 expression and low level of IKAP/ELP1 in Familial dysautonomia

Hervé

Ibrahim

2016

Disease Models &Amp; Mechanisms

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Familial dysautonomia (FD) is a rare neurodegenerative disease caused by a mutation in intron 20 of the IKBKAP gene (c.2204+6T>C), leading to tissue-specific skipping of exon 20 and a decrease in the synthesis of the encoded protein IKAP (also known as ELP1). Small non-coding RNAs known as microRNAs (miRNAs) are important post-transcriptional regulators of gene expression and play an essential role in the nervous system development and function. To better understand the neuronal specificity of IKAP loss, we examined expression of miRNAs in human olfactory ecto-mesenchymal stem cells (hOE-MSCs) from five control individuals and five FD patients. We profiled the expression of 373 miRNAs using microfluidics and reverse transcription coupled to quantitative PCR (RT-qPCR) on two biological replicate series of hOE-MSC cultures from healthy controls and FD patients. This led to the total identification of 26 dysregulated miRNAs in FD, validating the existence of a miRNA signature in FD. We then selected the nine most discriminant miRNAs for further analysis. The signaling pathways affected by these dysregulated miRNAs were largely within the nervous system. In addition, many targets of these dysregulated miRNAs had been previously demonstrated to be affected in FD models. Moreover, we found that four of our nine candidate miRNAs target the neuron-specific splicing factor NOVA1. We demonstrated that overexpression of miR-203a-3p leads to a decrease of NOVA1, counter-balanced by an increase of IKAP, supporting a potential interaction between NOVA1 and IKAP. Taken together, these results reinforce the choice of miRNAs as potential therapeutic targets and suggest that NOVA1 could be a regulator of FD pathophysiology.

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“…Newt anterior gradient protein has been shown to rescue regeneration in denervated newt limbs (Kumar et al, 2007), and despite some prominent species differences between axolotls and newts, which demonstrate a different recovery response to denervation (Liversage and McLaughlin, 1983) as well as a phylogenetically unique method of regenerating muscular tissues (Sandoval-Guzman et al, 2014;Tanaka et al, 2016), further exploration of the relationship between these two signaling pathways is necessary in order to characterize fully the underlying cause of nerve dependency in the axolotl limb. Given the conserved role of NRG1/ErbB2 signaling in the peripheral nerves as well as the burgeoning evidence of its necessity in other animal models of cardiac (Bersell et al, 2009;D'Uva et al, 2015;Gemberling et al, 2015) and peripheral nerve (Fricker et al, 2011;Ronchi et al, 2013Ronchi et al, , 2015 regeneration, elucidating the function and mechanism of this signaling pathway in the axolotl may have far-reaching impacts on the field of regenerative medicine.…”

Section: Discussionmentioning

confidence: 99%

Neuregulin-1 signaling is essential for nerve-dependent axolotl limb regeneration

et al. 2016

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The Mexican axolotl (Ambystoma mexicanum) is capable of fully regenerating amputated limbs, but denervation of the limb inhibits the formation of the post-injury proliferative mass called the blastema. The molecular basis behind this phenomenon remains poorly understood, but previous studies have suggested that nerves support regeneration via the secretion of essential growthpromoting factors. An essential nerve-derived factor must be found in the blastema, capable of rescuing regeneration in denervated limbs, and its inhibition must prevent regeneration. Here, we show that the neuronally secreted protein Neuregulin-1 (NRG1) fulfills all these criteria in the axolotl. Immunohistochemistry and in situ hybridization of NRG1 and its active receptor ErbB2 revealed that they are expressed in regenerating blastemas but lost upon denervation. NRG1 was localized to the wound epithelium prior to blastema formation and was later strongly expressed in proliferating blastemal cells. Supplementation by implantation of NRG1-soaked beads rescued regeneration to digits in denervated limbs, and pharmacological inhibition of NRG1 signaling reduced cell proliferation, blocked blastema formation and induced aberrant collagen deposition in fully innervated limbs. Taken together, our results show that nerve-dependent NRG1/ErbB2 signaling promotes blastemal proliferation in the regenerating limb and may play an essential role in blastema formation, thus providing insight into the longstanding question of why nerves are required for axolotl limb regeneration.

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The Neuregulin1/ErbB system is selectively regulated during peripheral nerve degeneration and regeneration

Cited by 43 publications

References 48 publications

Polycomb repression regulates Schwann cell proliferation and axon regeneration after nerve injury

Polycomb repression regulates Schwann cell proliferation and axon regeneration after nerve injury

MicroRNA screening identifies a link between NOVA1 expression and low level of IKAP/ELP1 in Familial dysautonomia

Neuregulin-1 signaling is essential for nerve-dependent axolotl limb regeneration

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