scholarly journals Neuregulin 1 type III reduces severity in a mouse model of Congenital Hypomyelinating Neuropathy

2018 ◽  
Author(s):  
Belin Sophie ◽  
Francesca Ornaghi ◽  
Ghjuvan'Ghjacumu Shackleford ◽  
Jie Wang ◽  
Cristina Scapin ◽  
...  
Keyword(s):  
Mouse Model ◽  
Cell Fate ◽  
Action Potentials ◽  
Sheath Thickness ◽  
Neuregulin 1 ◽  
Type Iii ◽  
Beneficial Effects ◽  
Axonal Protein ◽  
Congenital Hypomyelinating Neuropathy ◽  
Myelin Sheath Thickness

Myelin sheath thickness is precisely regulated and essential for rapid propagation of action potentials along myelinated axons. In the peripheral nervous system, extrinsic signals from the axonal protein neuregulin 1 type III regulate Schwann cell fate and myelination. Here we ask if modulating neuregulin 1 type III levels in neurons would restore myelination in a model of congenital hypomyelinating neuropathy (CHN). Using a mouse model of CHN, we rescued the myelination defects by early overexpression of neuregulin 1 type III. Surprisingly, the rescue was independent from the upregulation of Egr2 or essential myelin genes. Rather, we observed the activation of MAPK/ERK and other myelin genes such as peripheral myelin protein 2 (Pmp2) and oligodendrocyte myelin glycoprotein (Omg). We also confirmed that the permanent activation of MAPK/ERK in Schwann cells has detrimental effects on myelination. Our findings demonstrate that the modulation of axon-to-glial neuregulin 1 type III signaling has beneficial effects and restores myelination defects during development in a model of CHN.

scholarly journals Corrigendum: Neuregulin 1 type III improves peripheral nerve myelination in a mouse model of congenital hypomyelinating neuropathy

2019 ◽  
Vol 28 (13) ◽  
pp. 2282-2282
Author(s):  
Sophie Belin ◽  
Francesca Ornaghi ◽  
Ghjuvan’Ghjacumu Shackleford ◽  
Jie Wang ◽  
Cristina Scapin ◽  
...  
Keyword(s):  
Mouse Model ◽  
Peripheral Nerve ◽  
Neuregulin 1 ◽  
Type Iii ◽  
Congenital Hypomyelinating Neuropathy

scholarly journals Corrigendum: Neuregulin 1 type III improves peripheral nerve myelination in a mouse model of congenital hypomyelinating neuropathy

2019 ◽  
Vol 28 (10) ◽  
pp. 1752-1752
Author(s):  
Sophie Belin ◽  
Francesca Ornaghi ◽  
Ghjuvan’Ghjacumu Shackleford ◽  
Jie Wang ◽  
Cristina Scapin ◽  
...  
Keyword(s):  
Mouse Model ◽  
Peripheral Nerve ◽  
Neuregulin 1 ◽  
Type Iii ◽  
Congenital Hypomyelinating Neuropathy

scholarly journals Neuregulin 1 type III improves peripheral nerve myelination in a mouse model of congenital hypomyelinating neuropathy

2018 ◽  
Vol 28 (8) ◽  
pp. 1260-1273 ◽  
Author(s):  
Sophie Belin ◽  
Francesca Ornaghi ◽  
Ghjuvan’Ghjacumu Shackleford ◽  
Jie Wang ◽  
Cristina Scapin ◽  
...  
Keyword(s):  
Mouse Model ◽  
Peripheral Nerve ◽  
Neuregulin 1 ◽  
Type Iii ◽  
Congenital Hypomyelinating Neuropathy

scholarly journals Enhanced axonal neuregulin-1 type-III signaling ameliorates neurophysiology and hypomyelination in a Charcot–Marie–Tooth type 1B mouse model

2018 ◽  
Vol 28 (6) ◽  
pp. 992-1006 ◽  
Author(s):  
Cristina Scapin ◽  
Cinzia Ferri ◽  
Emanuela Pettinato ◽  
Desiree Zambroni ◽  
Francesca Bianchi ◽  
...  
Keyword(s):  
Mouse Model ◽  
Neuregulin 1 ◽  
Charcot Marie Tooth ◽  
Type Iii ◽  
Tooth Type

Axonal Neuregulin-1 Regulates Myelin Sheath Thickness

Science ◽  
2004 ◽  
Vol 304 (5671) ◽  
pp. 700-703 ◽  
Author(s):  
G. V. Michailov
Keyword(s):  
Myelin Sheath ◽  
Sheath Thickness ◽  
Neuregulin 1 ◽  
Myelin Sheath Thickness

scholarly journals Enhanced axonal Neuregulin-1 type-III signaling ameliorates disease severity in a CMT1B mouse model

2018 ◽  
Author(s):  
Cristina Scapin ◽  
Cinzia Ferri ◽  
Emanuela Pettinato ◽  
Desiree Zambroni ◽  
Francesca Bianchi ◽  
...  
Keyword(s):  
Mouse Model ◽  
Therapeutic Strategy ◽  
Genetic Disorders ◽  
Transcriptional Regulators ◽  
Morphological Parameters ◽  
Neuregulin 1 ◽  
Myelin Lipids ◽  
Type Iii ◽  
Downstream Signaling ◽  
Myelin Gene

ABSTRACTCharcot–Marie–Tooth neuropathies (CMTs) are a group of genetic disorders that affect the peripheral nervous system (PNS) with heterogeneous pathogenesis and no available treatment. Axonal Neuregulin 1 type III (Nrg1TIII) drives peripheral nerve myelination by activating downstream signaling pathways such as PI3K/Akt and MAPK/Erk that converge on master transcriptional regulators of myelin genes, such as Krox20. We reasoned that modulating Nrg1TIII activity may constitute a general therapeutic strategy to treat CMTs that are characterized by reduced levels of myelination. Here, we show that genetic overexpression of Nrg1TIII ameliorates neurophysiological and morphological parameters in a mouse model of demyelinating CMT1B, without exacerbating the toxic gain of function that underlies the neuropathy. Intriguingly, the mechanism appears not to be related to Krox20 or myelin gene upregulation, but rather to a beneficial rebalancing in the stoichiometry of myelin lipids and proteins. Finally, we provide proof of principle that stimulating Nrg1TIII signaling, by pharmacological suppression of the Nrg1TIII inhibitor TACE/ADAM17, also ameliorates the neuropathy. Thus, modulation of Nrg1TIII by TACE/ADAM17 inhibition may represent a general treatment for hypomyelinating neuropathies.

scholarly journals TrkB Agonist LM22A-4 Increases Oligodendroglial Populations During Myelin Repair in the Brain

2019 ◽  
Author(s):  
Huynh TH Nguyen ◽  
Rhiannon J Wood ◽  
Alexa R Prawdiuk ◽  
Sebastian GB Furness ◽  
Junhua Xiao ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Pharmacokinetic Profile ◽  
Dependent Manner ◽  
Sheath Thickness ◽  
Beneficial Effects ◽  
Central Demyelination ◽  
Cns Myelination ◽  
Trk B ◽  
The Brain ◽  
Myelin Sheath Thickness

AbstractThe neurotrophin, brain-derived neurotrophic factor (BDNF) promotes central nervous system (CNS) myelination during development and after injury. This is achieved via activation of oligodendrocyte-expressed tropomyosin-related kinase (Trk) B receptors. However, while administration of BDNF has shown beneficial effects, BDNF itself has a poor pharmacokinetic profile. Here, we compare two TrkB-targeted BDNF-mimetics, the structural-mimetic, tricyclic dimeric peptide-6 (TDP6) and the non-peptide small molecule TrkB agonist LM22A-4 in the cuprizone model of central demyelination in female mice. Both mimetics promoted remyelination, increasing myelin sheath thickness and oligodendrocyte densities after one-week recovery. Importantly, LM22A-4 exerts these effects in an oligodendroglial TrkB-dependent manner. However, analysis of TrkB signaling by LM22A-4 suggests rather than direct activation of TrkB, LM22A-4 exerts its effects via indirect transactivation of Trk receptors. Overall, these studies support the therapeutic strategy to selectively targeting TrkB activation to promote remyelination in the brain.

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