Neuregulin/ErbB Signaling in Developmental Myelin Formation and Nerve Repair

Birchmeier, Carmen; Bennett, David L.H.

doi:10.1016/bs.ctdb.2015.11.009

Cited by 51 publications

(38 citation statements)

References 127 publications

(159 reference statements)

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“…Schwann cell processes have been shown to guide regenerating axons, and it is possible that the impaired regeneration of unmyelinated axons that we observed is due to deficient physical interaction between axons and the elongated SC processes (Son and Thompson, 1995;Höke et al, 2006;Jessen and Mirsky, 2016). It is now recognized that the activation of a transcriptional repair program in SCs is a critical determinant of the success of axon regeneration (Painter et al, 2014;Jessen and Mirsky, 2016;Mindos et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…It is now recognized that the activation of a transcriptional repair program in SCs is a critical determinant of the success of axon regeneration (Painter et al, 2014;Jessen and Mirsky, 2016;Mindos et al, 2017). It is possible that uncoordinated MAPK activation leads to reduced trophic factor production by nonmyelinating SCs, leading to reduced reinnervation by sensory fibers.…”

Section: Discussionmentioning

confidence: 99%

“…During regeneration, a repair program is induced in myelinating and nonmyelinating SCs that supports regeneration (Arthur-Farraj et al, 2012;Jessen and Mirsky, 2016). The first phase of the injury response is Wallerian degeneration (WD), which involves axon destruction, dedifferentiation of SCs, activation of an inflammatory response, and phagocytosis of myelin debris (Chen et al, 2007;Jessen and Mirsky, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…Schwann cells start to proliferate, downregulate myelin gene expression, and adopt a repair phenotype. Subsequently, repair SCs differentiate again into mature SCs to generate myelin-forming and non-myelin-forming (Remak) cells (Arthur-Farraj et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Sustained MAPK/ERK Activation in Adult Schwann Cells Impairs Nerve Repair

et al. 2017

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The MAPK/ERK pathway has a critical role in PNS development. It is required for Schwann cell (SC) differentiation and myelination; sustained embryonic MAPK/ERK activation in SCs enhances myelin growth overcoming signals that normally end myelination. Excess activation of this pathway can be maladaptive as in adulthood acute strong activation of MAPK/ERK has been shown to cause SC dedifferentiation and demyelination. We used a mouse model (including male and female animals) in which the gain-of-function MEK1DD allele produces sustained MAPK/ERK activation in adult SCs, and we determined the impact of such activation on nerve repair. In the uninjured nerve, MAPK/ERK activation neither impaired myelin nor reactivated myelination. However, in the injured nerve it was detrimental and resulted in delayed repair and functional recovery. In the early phase of injury, the rate of myelin clearance was faster. Four weeks following injury, when nerve repair is normally advanced, myelinated axons of MEK1DD mutants demonstrated higher rates of myelin decompaction, a reduced number of Cajal bands. and decreased internodal length. We noted the presence of abnormal Remak bundles with long SCs processes and reduced numbers of C-fibers/Remak bundle. Both the total number of regenerating axons and the intraepidermal nerve fiber density in the skin were reduced. Sustained activation of MAPK/ERK in adult SCs is therefore deleterious to successful nerve repair, emphasizing the differences in the signaling processes coordinating nerve development and repair. Our results also underline the key role of SCs in axon regeneration and successful target reinnervation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sustained MAPK/ERK Activation in Adult Schwann Cells Impairs Nerve Repair

et al. 2017

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“…NRG1 in the axonal membrane regulates Schwann cell (SC) myelination during postnatal development [123]. In addition, the nrg1 gene encodes ARIA, Acetylcholine Receptor (AChR)-Inducing Activity, that plays a role in the development and maturation of the neuromuscular junction (NMJ) [456].…”

Section: Introductionmentioning

confidence: 99%

The Scaffolding Protein, Grb2-associated Binder-1, in Skeletal Muscles and Terminal Schwann Cells Regulates Postnatal Neuromuscular Synapse Maturation

et al. 2017

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The vertebrate neuromuscular junction (NMJ) is considered as a “tripartite synapse” consisting of a motor axon terminal, a muscle endplate, and terminal Schwann cells that envelope the motor axon terminal. The neuregulin 1 (NRG1)-ErbB2 signaling pathway plays an important role in the development of the NMJ. We previously showed that Grb2-associated binder 1 (Gab1), a scaffolding mediator of receptor tyrosine kinase signaling, is required for NRG1-induced peripheral nerve myelination. Here, we determined the role of Gab1 in the development of the NMJ using muscle-specific conditional Gab1 knockout mice. The mutant mice showed delayed postnatal maturation of the NMJ. Furthermore, the selective loss of the gab1 gene in terminal Schwann cells produced delayed synaptic elimination with abnormal morphology of the motor endplate, suggesting that Gab1 in both muscles and terminal Schwann cells is required for proper NMJ development. Gab1 in terminal Schwann cells appeared to regulate the number and process elongation of terminal Schwann cells during synaptic elimination. However, Gab2 knockout mice did not show any defects in the development of the NMJ. Considering the role of Gab1 in postnatal peripheral nerve myelination, our findings suggest that Gab1 is a pleiotropic and important component of NRG1 signals during postnatal development of the peripheral neuromuscular system.

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Developmental expression of Neuregulin‐3 in the rat central nervous system

Rahman

Weber

Labin

et al. 2018

J of Comparative Neurology

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Neuregulin‐3 (Nrg3) is a member of the Nrg family of growth factors identified as risk factors for schizophrenia. There are three Nrgs expressed in the nervous system (Nrg1‐3) and of these Nrg1 has been the best characterized. To set the groundwork for elucidating neural roles for Nrg3, we studied its expression in the rat brain at both the RNA and protein levels. Using an antibody developed against Nrg3, we observed a developmental increase of Nrg3 protein expression from embryonic stages to adulthood and determined that it carries O‐linked carbohydrates. In cortical neuronal cultures, transfected Neuro2a cells, and brain tissue sections Nrg3 protein was localized to the soma, neurites, and to the Golgi apparatus, where it is prominently expressed. Nrg3 was detected in excitatory, GABAergic and parvalbumin‐expressing inhibitory neurons while expression in glia was limited. Nrg3 mRNA and protein were widely expressed during both embryonic and postnatal ages. At E17, Nrg3 was detected within the cortical plate and ventricular zone suggesting possible roles in cell proliferation or migration. At postnatal ages, Nrg3 was abundantly expressed throughout the cerebral cortex and hippocampus. Multiple thalamic nuclei expressed Nrg3, while detection in the striatum was limited. In the cerebellum, Nrg3 was found in both Purkinje cells and granule neurons. In the rodent brain, Nrg3 is the most abundantly expressed of the Nrgs and its patterns of expression differ both temporally and spatially from that of Nrg1 and Nrg2. These findings suggest that Nrg3 plays roles that are distinct from the other Nrg family members.

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Neuregulin/ErbB Signaling in Developmental Myelin Formation and Nerve Repair

Cited by 51 publications

References 127 publications

Sustained MAPK/ERK Activation in Adult Schwann Cells Impairs Nerve Repair

Sustained MAPK/ERK Activation in Adult Schwann Cells Impairs Nerve Repair

The Scaffolding Protein, Grb2-associated Binder-1, in Skeletal Muscles and Terminal Schwann Cells Regulates Postnatal Neuromuscular Synapse Maturation

Developmental expression of Neuregulin‐3 in the rat central nervous system

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