Notch Signaling in Development, Tissue Homeostasis, and Disease

Abstract

Notch signaling is an evolutionarily highly conserved signaling mechanism, but in contrast to signaling pathways such as Wnt, Sonic Hedgehog, and BMP/TGF-β, Notch signaling occurs via cell-cell communication, where transmembrane ligands on one cell activate transmembrane receptors on a juxtaposed cell. Originally discovered through mutations in more than 100 yr ago, and with the first Notch gene cloned more than 30 yr ago, we are still gaining new insights into the broad effects of Notch signaling in organisms across the metazoan spectrum and its requirement for normal development of most organs in the body. In this review, we provide an overview of the Notch signaling mechanism at the molecular level and discuss how the pathway, which is architecturally quite simple, is able to engage in the control of cell fates in a broad variety of cell types. We discuss the current understanding of how Notch signaling can become derailed, either by direct mutations or by aberrant regulation, and the expanding spectrum of diseases and cancers that is a consequence of Notch dysregulation. Finally, we explore the emerging field of Notch in the control of tissue homeostasis, with examples from skin, liver, lung, intestine, and the vasculature.

Notch in skeletal physiology and disease

“…Interactions of Notch with its ligands lead to its proteolytic cleavage and release of the NICD, its translocation to the nucleus, where the NICD forms a complex with recombination signal-binding protein for Ig of κ region (RBPJκ) and mastermind-like (MAML) to regulate transcription [9, 10]. RBPJκ is also termed CBF1, Suppressor of hairless, Lag1 or CSL.…”

Gray Matter Heterotopia, Mental Retardation, Developmental Delay, Microcephaly, and Facial Dysmorphisms in a Boy with Ring Chromosome 6: A 10-Year Follow-Up and Literature Review

“…As it is known that although there are tons of causes contributing to mental retardation, genetic factors are of particular concern. Notch signaling is a conserved developmental pathway that has an essential role in development of multiple organ systems [Luxán et al, 2016;Siebel and Lendahl, 2017]. Recent research shows that the Notch signaling pathway is critical for proliferation, migration, and differentiation of the neurons during embryonic development [Byun et al, 2017], with DLL1 playing an important part in these physiological processes [Imai et al, 2015].…”

A tale of two clocks: phosphorylation of NICD by CDK s links cell cycle and segmentation clock

“…In this issue, Carrieri et al [1] show that phosphorylation of the Notch intracellular domain (NICD) by cyclin-dependent kinases (CDKs) suppresses Notch activity by promoting NICD turnover. In spite of a lack of signaling cascades or amplification, the pathway is utilized in a variety of dosage-sensitive developmental decisions, and pathway dysregulation is a major contributor to human disease and cancer [2]. S ignaling through the Notch pathway regulates a wide variety of developmental decisions across numerous metazoans.…”

“…In the absence of pathway amplification, the duration of the Notch signal is strongly influenced by numerous post-translational modifications that affect NICD stability [2]. Modes of regulation include the use of protein modifications to fine-tune ligand:receptor interactions, controlled protein trafficking to influence ligand/receptor presentation, and nuclear interactions that influence signaling outcomes.…”

“…In many contexts, recognition of NICD by this complex is mediated by FBXW7, a member of the F-box protein family that binds phosphorylated NICD [6]. The importance of this coordinated signal termination is reflected in numerous cancers where aberrant Notch signaling contributes to disease progression [2]. Mutations within the PEST domain of NICD have been observed in many cancers (notably T-cell acute lymphoblastic leukemia or T-ALL), most of which result in sustained Notch signaling due to increases in NICD stability.…”