RGMa inhibition promotes axonal growth and recovery after spinal cord injury

Abstract

Repulsive guidance molecule (RGM) is a protein implicated in both axonal guidance and neural tube closure. We report RGMa as a potent inhibitor of axon regeneration in the adult central nervous system (CNS). RGMa inhibits mammalian CNS neurite outgrowth by a mechanism dependent on the activation of the RhoA–Rho kinase pathway. RGMa expression is observed in oligodendrocytes, myelinated fibers, and neurons of the adult rat spinal cord and is induced around the injury site after spinal cord injury. We developed an antibody to RGMa that efficiently blocks the effect of RGMa in vitro. Intrathecal administration of the antibody to rats with thoracic spinal cord hemisection results in significant axonal growth of the corticospinal tract and improves functional recovery. Thus, RGMa plays an important role in limiting axonal regeneration after CNS injury and the RGMa antibody offers a possible therapeutic agent in clinical conditions characterized by a failure of CNS regeneration.

RGMA and IL21R show association with experimental inflammation and multiple sclerosis

“…The RGMA protein acts through the activation of a RhoA/Rho kinase-dependent pathway activation of myosin II. [42][43][44] Inhibition of Rho family functions has been shown to ameliorate EAE in rats, associated with promotion of myelin repair, inhibition of leukocyte infiltration into the central nervous system and a reduced axonal damage. [45][46][47] The strong expression of RhoA in active MS lesions and low expression in chronic MS lesions suggest that RhoA also has a role in MS. 47 We can thus hypothesize that variants of RGMA through differential regulation of RhoA result in different immune activation and disease outcome.…”

RGMs: Structural Insights, Molecular Regulation, and Downstream Signaling

“…The role of RGMs in axon guidance and neurite growth inhibition during development has been shown in frog and chick embryos, while in vivo evidence for the neurite growth inhibitory effects of RGMs in mammals is provided by the ability of RGM blockage to promote central nervous system (CNS) axon regeneration. Other important effects of RGM on cell death, migration, and differentiation have also been confirmed (Boxes 1 and 2) [11,13,[47][48][49]. The neurite growth inhibitory effects of RGMs have been studied extensively and rely on signaling by Rho-GTPases downstream of RGMa.…”

“…RGMs also serve as co-receptors for bone morphogenetic proteins (BMPs) ( Figure 1A) to regulate iron metabolism, skeletal development [5-10] and axon regeneration [11]. In addition to these physiological roles, and as discussed below, RGMs have been implicated in various diseases and are considered to be promising targets in the treatment of MS, spinal cord injury, stroke, anemia, and inflammation [5,[11][12][13][14][15].…”

“…Over the past few years, many groups have confirmed the ability of RGMs to induce axon repulsion, neurite growth inhibition, and growth cone collapse using different types of neuron [11,13,29,[43][44][45][46]. The role of RGMs in axon guidance and neurite growth inhibition during development has been shown in frog and chick embryos, while in vivo evidence for the neurite growth inhibitory effects of RGMs in mammals is provided by the ability of RGM blockage to promote central nervous system (CNS) axon regeneration.…”

“…RGMs also serve as co-receptors for bone morphogenetic proteins (BMPs) ( Figure 1A) to regulate iron metabolism, skeletal development [5-10] and axon regeneration [11]. In addition to these physiological roles, and as discussed below, RGMs have been implicated in various diseases and are considered to be promising targets in the treatment of MS, spinal cord injury, stroke, anemia, and inflammation [5,[11][12][13][14][15].Although the molecular mechanisms underlying the biological effects and signaling modes of RGMs have long remained unknown, recent work has unveiled several exciting and novel aspects of RGM processing, ligand-receptor interactions, and downstream signaling. These insights include high-resolution structural data of binary or tertiary protein complexes, the unique processing of RGMs into protein fragments with distinct functions, and the identification of a novel molecular mechanism to control ligand-induced ectodomain shedding of Neogenin.…”