RGMA

Official Full Name

repulsive guidance molecule BMP co-receptor a

Organism

Homo sapiens

GeneID

56963

Background

This gene encodes a member of the repulsive guidance molecule family. The encoded protein is a glycosylphosphatidylinositol-anchored glycoprotein that functions as an axon guidance protein in the developing and adult central nervous system. This protein may also function as a tumor suppressor in some cancers. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

Synonyms

RGM;

Bio Chemical Class

Repulsive guidance molecule family

Protein Sequence

MQPPRERLVVTGRAGWMGMGRGAGRSALGFWPTLAFLLCSFPAATSPCKILKCNSEFWSATSGSHAPASDDTPEFCAALRSYALCTRRTARTCRGDLAYHSAVHGIEDLMSQHNCSKDGPTSQPRLRTLPPAGDSQERSDSPEICHYEKSFHKHSATPNYTHCGLFGDPHLRTFTDRFQTCKVQGAWPLIDNNYLNVQVTNTPVLPGSAATATSKLTIIFKNFQECVDQKVYQAEMDELPAAFVDGSKNGGDKHGANSLKITEKVSGQHVEIQAKYIGTTIVVRQVGRYLTFAVRMPEEVVNAVEDWDSQGLYLCLRGCPLNQQIDFQAFHTNAEGTGARRLAAASPAPTAPETFPYETAVAKCKEKLPVEDLYYQACVFDLLTTGDVNFTLAAYYALEDVKMLHSNKDKLHLYDRTRDLPGRAAAGLPLAPRPLLGALVPLLALLPVFC

Open

Disease

Multiple sclerosis, Spine/trunk injury

Approved Drug

Clinical Trial Drug

1 +

Discontinued Drug

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Detailed Information

The RGMA (Repulsive Guidance Molecule BMP Co-Receptor A) gene encodes a glycosylphosphatidylinositol (GPI)-anchored membrane protein belonging to the repulsive guidance molecule (RGM) family. Its protein structure includes an N-terminal signal peptide, an RGD motif that mediates cell adhesion, and a C-terminal GPI-anchoring domain. RGMA is highly expressed in the embryonic nervous system, where it regulates axonal guidance and neural tube closure through interactions with the receptor Neogenin (NEO1) and bone morphogenetic proteins (BMPs). In the adult brain, RGMA is expressed in neurons, astrocytes, and microglia, contributing to synaptic plasticity and maintenance of blood-brain barrier homeostasis.

Physiological Function and Molecular Mechanisms

RGMA plays a central role in spatial guidance and structural stability of the nervous system. Its interaction with Neogenin activates downstream signaling cascades: through the UNC5B-ARHGEF12/LARG-PTK2/FAK1 pathway, it activates RHOA-ROCK1 to induce growth cone collapse, and it inhibits the HRAS-PTK2/FAK1-AKT1 pathway, leading to HRAS inactivation and suppression of neuronal branching. As a BMP2/4 co-receptor, RGMA enhances BMP binding to its receptors and activates the SMAD1/5/8 pathway, contributing to dorsal neural tube morphogenesis. In the adult hippocampus, RGMA regulates dendritic spine remodeling through the LIMK1-cofilin pathway, affecting learning and memory.

Pathological Mechanisms and Disease Associations

In neurodegenerative diseases, RGMA levels are significantly elevated in the cerebrospinal fluid (CSF) of amyotrophic lateral sclerosis (ALS) patients and correlate with symptom severity. RGMA contributes to pathology by disrupting blood-brain barrier integrity, facilitating entry of abnormal proteins such as SOD1 aggregates into neurons, and activating microglia to release IL-1β, promoting motor neuron apoptosis. In animal models, anti-RGMA antibodies reduce ubiquitin-positive aggregates and extend survival. In autoimmune conditions like neuromyelitis optica (NMO), RGMA recruits neutrophils, amplifying lesion damage through reactive oxygen species-induced astrocyte death, while anti-RGMA antibody treatment reduces neutrophil infiltration and improves motor function. Following ischemic brain injury, RGMA expression in the infarcted region triples within 6–24 hours, inhibiting axonal regeneration and promoting glial scar formation via ROCK1 pathway activation. In psychiatric and oncological contexts, rare RGMA variants are linked to abnormal synaptic pruning in autism spectrum disorder, and RGMA suppresses CD8+ T cell infiltration in gliomas via BMP-SMAD signaling, promoting immune tolerance.

Figure 1. RGMa signaling in different cell types, illustrating Rho-GTP–mediated growth cone collapse in neurons and BMP/SMAD–dependent hepcidin induction in liver cells. (Fujii T, et al., 2024)

Clinical Applications and Translational Research

RGMA has potential as a diagnostic biomarker: CSF RGMA levels in ALS patients are doubled compared with healthy controls and correlate with disease progression, providing prognostic information. Anti-RGMA antibodies have shown therapeutic potential in multiple neurological disease models: in NMO, intrathecal administration reduces pain behaviors and spinal neutrophil infiltration; in stroke models of non-human primates, antibodies enhance motor recovery more effectively than conventional neurotrophic factors; in ALS SOD1 mice, antibody treatment prolongs survival by approximately 25% in a dose-dependent manner. The first anti-RGMA antibody, elezanumab, has entered phase II clinical trials for multiple sclerosis. Small molecule inhibitors such as butylphthalide, approved in China for ischemic stroke, partially exert effects by suppressing RGMA expression, improving neurological scores, though specificity remains limited.

Challenges and Future Directions

Targeting RGMA faces key challenges, including its dual role in repulsive guidance and BMP signaling, where inhibition of repulsion may interfere with BMP-mediated tissue repair. Blood-brain barrier penetration necessitates intrathecal administration of antibodies, reducing patient compliance, which may be addressed by nanocarriers or bispecific antibodies targeting TfR1/RGMA. Therapeutic efficacy is also disease-stage dependent; early RGMA inhibition delays onset in ALS models, whereas late intervention exacerbates neuroinflammation, highlighting the importance of treatment timing. Future research aims to clarify RGMA’s cell-type specific roles in neurons, glial cells, and immune cells, develop tissue-targeted antibodies capable of crossing the blood-brain barrier, and explore its role in chronic pain due to its receptor Neogenin’s involvement in opioid tolerance. As a convergence point for neural injury and immune-mediated inflammation, RGMA represents a promising target for advancing therapies in neural repair and regeneration.

Reference

Fujita Y, Yamashita T. The roles of RGMa-neogenin signaling in inflammation and angiogenesis. Inflamm Regen. 2017 Mar 8;37:6.
Yuan X, Shen G, Xiao H, et al. Netrin-1 and RGMa: Novel Regulators of Atherosclerosis-Related Diseases. Cardiovasc Drugs Ther. 2025 Feb;39(1):211-219.
Tseriotis VS, Liampas A, Lazaridou IZ, et al. Repulsive Guidance Molecule-A as a Therapeutic Target Across Neurological Disorders: An Update. Int J Mol Sci. 2025 Mar 30;26(7):3221.
Fujii T, Kobayashi K, Kaneko M, et al. RGM Family Involved in the Regulation of Hepcidin Expression in Anemia of Chronic Disease. Immuno (Basel). 2024;4(3):266–285.

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