The Notch signaling pathway in skeletal muscle health and disease

Abstract

The Notch signaling pathway is a key regulator of skeletal muscle development and regeneration. Over the past decade, the discoveries of three new muscle disease genes have added a new dimension to the relationship between the Notch signaling pathway and skeletal muscle: MEGF10, POGLUT1, and JAG2. We review the clinical syndromes associated with pathogenic variants in each of these genes, known molecular and cellular functions of their protein products with a particular focus on the Notch signaling pathway, and potential novel therapeutic targets that may emerge from further investigations of these diseases. The phenotypes associated with two of these genes, POGLUT1 and JAG2, clearly fall within the realm of muscular dystrophy, whereas the third, MEGF10, is associated with a congenital myopathy/muscular dystrophy overlap syndrome classically known as early-onset myopathy, areflexia, respiratory distress, and dysphagia. JAG2 is a canonical Notch ligand, POGLUT1 glycosylates the extracellular domain of Notch receptors, and MEGF10 interacts with the intracellular domain of NOTCH1. Additional genes and their encoded proteins relevant to muscle function and disease with links to the Notch signaling pathway include TRIM32, ATP2A1 (SERCA1), JAG1, PAX7, and NOTCH2NLC. There is enormous potential to identify convergent mechanisms of skeletal muscle disease and new therapeutic targets through further investigations of the Notch signaling pathway in the context of skeletal muscle development, maintenance, and disease.

Keywords: JAG2; MEGF10; Notch signaling pathway; POGLUT1; muscular dystrophy.

FIGURE 1

Diagram of the Notch signaling pathway showing putative interactions between Notch receptors and several key molecules of interest: JAG1/JAG2 (A); MEGF12, also known as JEDI (B); and MEGF10 (C). Several key steps in the interaction between a Notch receptor and a ligand are numbered in the diagram. Abbreviations: ADAM10, A Disintegrin and metalloproteinase domain–containing protein 10; CSL, CBF‐1/RBPJ‐κ, Suppressor of Hairless, LAG‐1; JAG1/2, Jagged1/2; MAML1, mastermind‐like1; MEGF10/12, multiple epidermal growth factor–like domains protein 10/12; NECD, notch extracellular domain; NICD, Notch intracellular domain; TM, transmembrane domain.

FIGURE 2

A, Diagram of pathogenic variants in MEGF10 mutations categorized by variant type: nonsense, frameshift, missense, and splice site. Variants’ positions were determined using the reference human MEGF10 transcript variant 1 (NM_032446.3). B, Diagram of amino acids in the human MEGF10 protein affected by pathogenic variants.

FIGURE 3

Isoforms of the Megf10 protein in human, mouse, zebrafish, and fruit fly. Each isoform has an EMI domain, a Delta and OS M‐11‐like (DSL) motif, epidermal growth factor–like domains, a transmembrane domain, and an Asn‐Pro‐x‐Tyr (NPxY) domain. Immunoreceptor tyrosine‐based activator motif (ITAM) domain 2 is only conserved in human, mouse, and zebrafish. ITAM domain 1 is very well conserved across species. Drpr A has an immunoreceptor tyrosine‐based inhibitory motif (ITIM) domain, which is not present in the other isoforms or species.

FIGURE 4

A, Pathogenic variants in POGLUT1 are predominantly missense changes distributed widely throughout the gene. B, Amino acid changes corresponding to the nucleotide changes in A. The predominance of missense variants indicates that the protein is sensitive to an array of conformational changes.

FIGURE 5

Conservation of key domains of POGLUT1 across species, including the signal peptide sequence, CAP10 domain, and the endoplasmic reticulum (ER) retention sequence.

FIGURE 6

Key domains of the JAG2 (Jagged2) protein are conserved across multiple species.

FIGURE 7

Schematic diagram of Notch signaling pathway proteins directly related to human skeletal muscle disease in the muscle fiber vs capillary (left) accompanied by a diagram showing the localization of orthologous proteins in Drosophila (right). Human and Drosophila orthologous pairs include the proteins JAG2 (Jagged2) and Ser (Serrate), MEGF10 and Drpr (Draper), and HNRNP L and Sm (Smooth). The question mark denotes the potential presence of Megf10 in endothelial cells.