Motor neurons and the generation of spinal motor neuron diversity

Abstract

Motor neurons (MNs) are neuronal cells located in the central nervous system (CNS) controlling a variety of downstream targets. This function infers the existence of MN subtypes matching the identity of the targets they innervate. To illustrate the mechanism involved in the generation of cellular diversity and the acquisition of specific identity, this review will focus on spinal MNs (SpMNs) that have been the core of significant work and discoveries during the last decades. SpMNs are responsible for the contraction of effector muscles in the periphery. Humans possess more than 500 different skeletal muscles capable to work in a precise time and space coordination to generate complex movements such as walking or grasping. To ensure such refined coordination, SpMNs must retain the identity of the muscle they innervate. Within the last two decades, scientists around the world have produced considerable efforts to elucidate several critical steps of SpMNs differentiation. During development, SpMNs emerge from dividing progenitor cells located in the medial portion of the ventral neural tube. MN identities are established by patterning cues working in cooperation with intrinsic sets of transcription factors. As the embryo develop, MNs further differentiate in a stepwise manner to form compact anatomical groups termed pools connecting to a unique muscle target. MN pools are not homogeneous and comprise subtypes according to the muscle fibers they innervate. This article aims to provide a global view of MN classification as well as an up-to-date review of the molecular mechanisms involved in the generation of SpMN diversity. Remaining conundrums will be discussed since a complete understanding of those mechanisms constitutes the foundation required for the elaboration of prospective MN regeneration therapies.

Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations

“…Gars C201R/+ mice do not show loss of motor neuron cell bodies up to at least 4 mo in the lumbar spinal cord (12). α-Motor neurons innervate force-generating extrafusal muscle fibers, whereas the smaller γ-motor nerves innervate intrafusal fibers of muscle spindles (40). The presence of NeuN distinguishes between α-and γ-motor neurons (SI Appendix , Fig.…”

Modeling ALS with motor neurons derived from human induced pluripotent stem cells

“…Current protocols for directing pluripotent stem cells (PSCs) toward LMNs are built upon extensive neural specification studies conducted in amphibian, chick and mouse embryos 5–7 ; (reviewed by Jessell 8 , Kanning 9 and Stifani 10 ). During gastrulation (Figure 1, i), ectodermal cells are initially fated along the anterior-posterior axis by activation of fibroblast growth factors (FGFs) and Wingless-type MMTV integration site family members (Wnts) (Figure 1, ii).…”

“…Strategies to generate and quantify hPSC-LMN diversity (reviewed by Stifani 10 ) beyond pan-LMN markers are necessary to assess vulnerabilities specific to LMN subtypes in in vitro models of ALS 55 . Investigators have begun to characterize hPSC-LMNs as limb-innervating lateral motor column (LMC) and axial muscle-innervating medial motor column (MMC) based on transcriptional profiles observed in developing mouse embryos 56 .…”

Neuromuscular Junction Impairment in Amyotrophic Lateral Sclerosis: Reassessing the Role of Acetylcholinesterase

“…MNs are generally divided into two classes: fast-fatigable (FF) and slow (S) (Heckman and Enoka, 2012). A third kind of MNs exists, the fast-fatigue-resistant (FFR), considered an intermediate phenotype between FF and S MNs, but little is known about its physiology (Stifani, 2014). In hSOD1 G93A mouse the FF MNs synapses degenerates while S-MNs synapses remain preserved (Pun et al, 2006).…”