The synaptic receptor Lrp4 promotes peripheral nerve regeneration

Gribble, Katherine D.; Walker, Lauren J.; Saint-Amant, Louis; Kuwada, John Y.; Granato, Michael

doi:10.1038/s41467-018-04806-4

Cited by 39 publications

(44 citation statements)

References 69 publications

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“…Protein kinase B (PKB/Akt) and mTORC1 (mammalian Target of Rapamycin Complex 1) have been implicated in regulating muscle homeostasis and maintaining NMJs after nerve injury in mice (Castets et al, 2019). Other key elements of synapse development such as Col13a1 (Zainul et al, 2018) and LRP4 (Gribble et al, 2018) have also been involved in promoting peripheral nerve regeneration. Finally, tSCs play a key role in reinnervation by guiding axons through the extension of their processes (Son and Thompson, 1995) and retracting processes from territory they previously occupied within the endplate (Kang et al, 2014).…”

Section: Regeneration Of the Nmjmentioning

confidence: 99%

The Neuromuscular Junction in Health and Disease: Molecular Mechanisms Governing Synaptic Formation and Homeostasis

Cruz

Cossins

Beeson

et al. 2020

Front. Mol. Neurosci.

124

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The neuromuscular junction (NMJ) is a highly specialized synapse between a motor neuron nerve terminal and its muscle fiber that are responsible for converting electrical impulses generated by the motor neuron into electrical activity in the muscle fibers. On arrival of the motor nerve action potential, calcium enters the presynaptic terminal, which leads to the release of the neurotransmitter acetylcholine (ACh). ACh crosses the synaptic gap and binds to ACh receptors (AChRs) tightly clustered on the surface of the muscle fiber; this leads to the endplate potential which initiates the muscle action potential that results in muscle contraction. This is a simplified version of the events in neuromuscular transmission that take place within milliseconds, and are dependent on a tiny but highly structured NMJ. Much of this review is devoted to describing in more detail the development, maturation, maintenance and regeneration of the NMJ, but first we describe briefly the most important molecules involved and the conditions that affect their numbers and function. Most important clinically worldwide, are myasthenia gravis (MG), the Lambert-Eaton myasthenic syndrome (LEMS) and congenital myasthenic syndromes (CMS), each of which causes specific molecular defects. In addition, we mention the neurotoxins from bacteria, snakes and many other species that interfere with neuromuscular transmission and cause potentially fatal diseases, but have also provided useful probes for investigating neuromuscular transmission. There are also changes in NMJ structure and function in motor neuron disease, spinal muscle atrophy and sarcopenia that are likely to be secondary but might provide treatment targets. The NMJ is one of the best studied and most disease-prone synapses in the nervous system and it is amenable to in vivo and ex vivo investigation and to systemic therapies that can help restore normal function.

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Section: Regeneration Of the Nmjmentioning

confidence: 99%

The Neuromuscular Junction in Health and Disease: Molecular Mechanisms Governing Synaptic Formation and Homeostasis

Cruz

Cossins

Beeson

et al. 2020

Front. Mol. Neurosci.

124

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“…Other monocyte DEGs in SV stroke are GLP2R, which is involved in glucose homeostasis and has been linked to risk of type 2 diabetes 60,61 ; and LRP4 which responds to ischemia in astrocytes, and in peripheral axons promotes nerve regeneration. 62,63 Interestingly, under normal conditions, there is no expression of this gene in monocytes. 64 The same was true for FGD5, a neovascularization inhibitor 65 ; HHIP, which is associated with prediabetes, 66 and PERM1, a gene involved in mitochondrial biogenesis whose expression pattern is altered with exercise.…”

Section: Monocyte Gene Response To Ischemic Stroke Is Down-regulatedmentioning

confidence: 99%

Distinct peripheral blood monocyte and neutrophil transcriptional programs following intracerebral hemorrhage and different etiologies of ischemic stroke

Carmona-Mora

Ander

Jickling

et al. 2020

J Cereb Blood Flow Metab

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Understanding cell-specific transcriptome responses following intracerebral hemorrhage (ICH) and ischemic stroke (IS) will improve knowledge of the immune response to brain injury. Transcriptomic profiles of 141 samples from 48 subjects with ICH, different IS etiologies, and vascular risk factor controls were characterized using RNA-seq in isolated neutrophils, monocytes and whole blood. In both IS and ICH, monocyte genes were down-regulated, whereas neutrophil gene expression changes were generally up-regulated. The monocyte down-regulated response to ICH included innate, adaptive immune, dendritic, NK cell and atherosclerosis signaling. Neutrophil responses to ICH included tRNA charging, mitochondrial dysfunction, and ER stress pathways. Common monocyte and neutrophil responses to ICH included interferon signaling, neuroinflammation, death receptor signaling, and NFAT pathways. Suppressed monocyte responses to IS included interferon and dendritic cell maturation signaling, phagosome formation, and IL-15 signaling. Activated neutrophil responses to IS included oxidative phosphorylation, mTOR, BMP, growth factor signaling, and calpain proteases-mediated blood–brain barrier (BBB) dysfunction. Common monocyte and neutrophil responses to IS included JAK1, JAK3, STAT3, and thrombopoietin signaling. Cell-type and cause-specific approaches will assist the search for future IS and ICH biomarkers and treatments.

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“…1). However, since the first regrowing motor axon sprouts emerge from the proximal stump several hours later (around 9 h or 540 min after transection) 49 , reduced regrowth of phr mutant peripheral motor nerves cannot be caused by the intact distal stump. In phr mutant CNS Mauthner axons however, we did not observe a delay in Wallerian degeneration.…”

Section: Resultsmentioning

confidence: 99%

The ubiquitin ligase PHR promotes directional regrowth of spinal zebrafish axons

et al. 2019

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To reconnect with their synaptic targets, severed axons need to regrow robustly and directionally along the pre-lesional trajectory. While mechanisms directing axonal regrowth are poorly understood, several proteins direct developmental axon outgrowth, including the ubiquitin ligase PHR (Mycbp2). Invertebrate PHR also limits regrowth of injured axons, whereas its role in vertebrate axonal regrowth remains elusive. Here we took advantage of the high regrowth capacity of spinal zebrafish axons and observed robust and directional regrowth following laser transection of spinal Mauthner axons. We found that PHR directs regrowing axons along the pre-lesional trajectory and across the transection site. At the transection site, initial regrowth of wild-type axons was multidirectional. Over time, misdirected sprouts were corrected in a PHR-dependent manner. Ablation of cyfip2 , known to promote F-actin-polymerization and pharmacological inhibition of JNK reduced misdirected regrowth of PHR-deficient axons, suggesting that PHR controls directional Mauthner axonal regrowth through cyfip2 - and JNK-dependent pathways.

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The synaptic receptor Lrp4 promotes peripheral nerve regeneration

Cited by 39 publications

References 69 publications

The Neuromuscular Junction in Health and Disease: Molecular Mechanisms Governing Synaptic Formation and Homeostasis

The Neuromuscular Junction in Health and Disease: Molecular Mechanisms Governing Synaptic Formation and Homeostasis

Distinct peripheral blood monocyte and neutrophil transcriptional programs following intracerebral hemorrhage and different etiologies of ischemic stroke

The ubiquitin ligase PHR promotes directional regrowth of spinal zebrafish axons

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