ErbB receptor signaling directly controls oligodendrocyte progenitor cell transformation and spontaneous remyelination after spinal cord injury

We recently discovered a novel role for neuregulin-1 (Nrg1) signaling in mediating spontaneous regenerative processes and functional repair after spinal cord injury (SCI). We revealed that Nrg1 is the molecular signal responsible for spontaneous functional remyelination of dorsal column axons by peripheral nervous system (PNS)-like Schwann cells after SCI. Here, we investigate whether Nrg1/ErbB signaling controls the unusual transformation of centrally derived progenitor cells into these functional myelinating Schwann cells after SCI using a fate-mapping/lineage tracing approach. Specific ablation of Nrg1-ErbB receptors in central platelet-derived growth factor receptor alpha (PDGFR)-derived lineage cells (using PDGFRCreERT2/Tomato-red reporter mice crossed with ErbB3fl/fl/ErbB4fl/fl mice) led to a dramatic reduction in P0-positive remyelination in the dorsal columns following spinal contusion injury. Central myelination, assessed by Olig2 and proteolipid protein expression, was unchanged. Loss of ErbB signaling in PDGFR lineage cells also significantly impacted the degree of spontaneous locomotor recovery after SCI, particularly in tests dependent on proprioception. These data have important implications, namely (a) cells from the PDGFR-expressing progenitor lineage (which are presumably oligodendrocyte progenitor cells, OPCs) can differentiate into remyelinating PNS-like Schwann cells after traumatic SCI, (b) this process is controlled by ErbB tyrosine kinase signaling, and (c) this endogenous repair mechanism has significant consequences for functional recovery after SCI. Thus, ErbB tyrosine kinase receptor signaling directly controls the transformation of OPCs from the PDGFR-expressing lineage into PNS-like functional remyelinating Schwann cells after SCI.

Multiple roles of mouse Numb in tuning developmental cell fates

Michel Aguet, Lukas Sommer

BACKGROUND: Notch signaling regulates multiple differentiation processes and cell fate decisions during both invertebrate and vertebrate development. Numb encodes an intracellular protein that was shown in Drosophila to antagonize Notch signaling at binary cell fate decisions of certain cell lineages. Although overexpression experiments suggested that Numb might also antagonize some Notch activity in vertebrates, the developmental processes in which Numb is involved remained elusive. RESULTS: We generated mice with a homozygous inactivation of Numb. These mice died before embryonic day E11.5, probably because of defects in angiogenic remodeling and placental dysfunction. Mutant embryos had an open anterior neural tube and impaired neuronal differentiation within the developing cranial central nervous system (CNS). In the developing spinal cord, the number of differentiated motoneurons was reduced. Within the peripheral nervous system (PNS), ganglia of cranial sensory neurons were formed. Trunk neural crest cells migrated and differentiated into sympathetic neurons. In contrast, a selective differentiation anomaly was observed in dorsal root ganglia, where neural crest--derived progenitor cells had migrated normally to form ganglionic structures, but failed to differentiate into sensory neurons. CONCLUSIONS: Mouse Numb is involved in multiple developmental processes and required for cell fate tuning in a variety of lineages. In the nervous system, Numb is required for the generation of a large subset of neuronal lineages. The restricted requirement of Numb during neural development in the mouse suggests that in some neuronal lineages, Notch signaling may be regulated independently of Numb.

2001

Deficiency in monocarboxylate transporter 1 (MCT1) in mice delays regeneration of peripheral nerves following sciatic nerve crush

Lin Jin, Sylvain Eric Lengacher, Pierre Magistretti, Luc Pellerin

Peripheral nerve regeneration following injury occurs spontaneously, but many of the processes require metabolic energy. The mechanism of energy supply to axons has not previously been determined. In the central nervous system, monocarboxylate transporter 1 (MCT1), expressed in oligodendroglia, is critical for supplying lactate or other energy metabolites to axons. In the current study, MCT1 is shown to localize within the peripheral nervous system to perineurial cells, dorsal root ganglion neurons, and Schwann cells by MCT1 immunofluorescence in wild-type mice and tdTomato fluorescence in MCT1 BAC reporter mice. To investigate whether MCT1 is necessary for peripheral nerve regeneration, sciatic nerves of MCT1 heterozygous null mice are crushed and peripheral nerve regeneration was quantified electrophysiologically and anatomically. Compound muscle action potential (CMAP) recovery is delayed from a median of 21 days in wild-type mice to greater than 38 days in MCT1 heterozygote null mice. In fact, half of the MCT1 heterozygote null mice have no recovery of CMAP at 42 days, while all of the wild-type mice recovered. In addition, muscle fibers remain 40% more atrophic and neuromuscular junctions 40% more denervated at 42 days post-crush in the MCT1 heterozygote null mice than wild-type mice. The delay in nerve regeneration is not only in motor axons, as the number of regenerated axons in the sural sensory nerve of MCT1 heterozygote null mice at 4 weeks and tibial mixed sensory and motor nerve at 3 weeks is also significantly reduced compared to wild-type mice. This delay in regeneration may be partly due to failed Schwann cell function, as there is reduced early phagocytosis of myelin debris and remyelination of axon segments. These data for the first time demonstrate that MCT1 is critical for regeneration of both sensory and motor axons in mice following sciatic nerve crush. (C) 2014 Elsevier Inc. All rights reserved.

Elsevier2015

Soft multimodal neural interfaces for unravelling sensory neurological circuits

Frédéric Pierre Gérald Michoud

Diseases or injuries affecting the nervous system can dramatically disrupt the quality of life. Despite extensive efforts towards treating dysfunctional nervous systems, the pharmacological and electrical approaches generally involved lack the temporal and spatial resolutions needed to selectively modulate neural activity. The somatosensory system intertwines numerous neural populations with distinct functionalities, whose specific neuromodulation would be beneficial for the alleviation of chronic pain and the restoration of locomotion after spinal cord injury. This thesis aims to develop a new generation of electrical and optical neural interfaces to selectively parse the somatosensory system. At the peripheral nerve level, we proposed an optical cuff and a wireless optoelectronic system to deliver epineural optogenetic stimulations in freely-behaving mice. The former consists of a soft elastomeric cuff wrapped around the sciatic nerve and integrated into a thin optic fiber. We demonstrated consistent orderly recruitment of motor units with optical stimulations in Thy1::ChR2 mice. This optocuff represents a simple, yet efficient, solution to probe the peripheral nervous system using optogenetics. However, untethered experimentation offers more versatility for fine neuromodulation applications. Within this framework, we developed a system comprising an ultra-miniaturized wireless stimulator and a soft circumneural ÎŒ-LED array to deliver optogenetic stimulations to the sciatic nerve. This optoelectronic implant conformed to the nerveâs morphology and complied with its dynamic motion. We demonstrated the systemâs efficacy via optogenetic activation of nociceptors in TRPV1::ChR2 mice. Both the optocuff and the wireless optoelectronic system exhibited seamless bio-integration after chronic implantation, thus highlighting the benefits of soft neurotechnology for interfacing with peripheral nerves. At the spinal level, we introduced a transversal electrode array for multipolar epidural stimulation of the spinal cord. The silicone materials used for its fabrication conferred this implant with mechanical properties matching the dura mater, allowing for remarkable biocompatibility following long-term implantation. Based on the spinal cord anatomy, this implant displayed a wide distribution of neural electrodes at a single spinal level, which enabled selective recruit- ment of posterior spinal roots. This novel paradigm was implemented to a spatio-temporal stimulation protocol and demonstrated potential in restoring locomotion after spinal cord injury. Finally, we reported a soft ÎŒ-LED array to deliver optogenetic stimulations in deep spinal structures. Insertion of this thin (< 100 ÎŒm) optoelectronic implant in the mouse epidural space did not provoke tissue damages while maintaining its functionality with normal dynamic motion. As a proof-of-principle, we showed concomitant electromyographic activity with epidural optical stimulations in Thy1::ChR2 mice. This premise offers a large range of opportunities to probe the spinal circuits involved in sensory processing and locomotion. In conclusion, these selective neural interfaces are proposed as innovative tools to unravel peripheral and spinal neural circuits. This venue will support the development of relevant clinical treatments for tackling dysfunctional neural systems. Eventually, these implant concepts pave the way for the translation of fine neuromodulation therapies in humans.