Delta-induced Notch Signaling Mediated by RBP-J Inhibits MyoD Expression and Myogenesis

Abstract

Signaling induced by interaction between the receptor Notch and its ligand Delta plays an important role in cell fate determination in vertebrates as well as invertebrates. Vertebrate Notch signaling has been investigated using its constitutively active form, i.e. the truncated intracellular region which is believed to mimic Notch-Delta signaling by interaction with a DNA-binding protein RBP-J. However, the molecular mechanism for Notch signaling triggered by ligand binding, which leads to inhibition of differentiation, is not clear. We have established a myeloma cell line expressing mouse Delta1 on its cell surface which can block muscle differentiation by co-culture with C2C12 muscle progenitor cells. We showed that Delta-induced Notch signaling

MyoD and E-protein heterodimers switch rhabdomyosarcoma cells from an arrested myoblast phase to a differentiated state

“…Therefore, disruption of a balanced equilibrium between bHLH factors that dimerize with E-proteins could result in an excess of repressive rather than active complexes when the full activation of MyoD is required for terminal differentiation. Coexisting with these bHLH factors are multiple other inhibitors of MyoD activity, Pax3 and Pax7, and activated inhibitory signaling pathways, such as Ras (Marampon et al 2006;Langenau et al 2007) and Notch pathways (Kuroda et al 1999;Nofziger et al 1999).…”

“…In contrast, the HLH protein Id and the bHLH protein Musculin (MSC)/MyoR can prevent MyoD activity by forming antagonistic dimers with E-proteins (Benezra et al 1990;Lu et al 1999; for review, see Massari and Murre 2000;Berkes and Tapscott 2005). In addition, notch signaling induces expression of the hairy enhancer of split (HES) family of bHLH proteins, which can directly inhibit gene expression by recruiting corepressors, or through interaction with E-proteins (Kuroda et al 1999;Nofziger et al 1999). Despite these and many other distinct mechanisms of inhibiting the MyoD-mediated myogenic program of terminal differentiation, the switch from a proliferative myoblast to a terminally differentiated myocyte appears to be a highly regulated transition and MyoD/Myf5 are nodal points that integrate the balance between multiple growth and differentiation signals (Weintraub et al 1991).…”

Regulation of Notch1 Signaling by Delta-like Ligand 1 Intracellular Domain through Physical Interaction

“…Several downstream targets of Notch signaling have also been identified, including Enhancer of split [E(spl)] complex genes and the mammalian homologues of the Hairy and E(spl) genes, Hes1 and Hes5 (Mumm and Kopan, 2000). These basic helix-loop-helix (bHLH) proteins antagonize other bHLH factors, such as MyoD, which induces muscle differentiation (Hirsinger et al, 2001;Jin et al, 2009;Kageyama et al, 2000;Kopan et al, 1994;Kuroda et al, 1999).…”

Inhibition of Notch1 signaling by Runx2 during osteoblast differentiation

“…(8)(9)(10)(11)(12) These basic helix-loop-helix (bHLH) proteins antagonize other bHLH factors, such as MyoD, which induces muscle differentiation. (13)(14)(15)(16) Runx2/Cbfa1/Pebp2aA (Runt-related transcription factor) is an essential transactivator for osteoblast differentiation and bone formation and is crucial for regulating the expression of bone-specific genes. (17,18) Runx2 controls lineage commitment, proliferation, and anabolic functions of osteoblasts as the subnuclear effector of multiple signaling axes.…”