An overview of notch signaling in adult tissue renewal and maintenance

Abstract

The Notch pathway is a critical mediator of short-range cell-cell communication that is reiteratively used to regulate a diverse array of cellular processes during embryonic development and the renewal and maintenance of adult tissues. Most Notch-dependent processes utilize a core signaling mechanism that is dependent on regulated intramembrane proteolysis: Upon ligand binding, Notch receptors undergo ectodomain shedding by ADAM metalloproteases, followed by γ-secretase-mediated intramembrane proteolysis. This releases the Notch intracellular domain, which translocates to the nucleus to activate transcription. In this review, we highlight the roles of Notch signaling particularly in self-renewing tissues in adults and several human diseases and raise some key considerations when targeting ADAMs and γ-secretase as disease-modifying strategies for Alzheimer's Disease.

Figure 1

Overview of the Notch signaling pathway. (a) Schematic depiction of mammalian Notch receptors and DSL ligands. Notch receptors are large single-pass Type I membrane proteins. The extracellular domain has 29-36 epidermal growth factor (EGF) repeats, followed by the conserved Lin12-Notch repeats (LNR: light green) and a heterodimerization domain (HD). The LNR and HD domains constitute the Negative regulatory region (NRR). The single transmembrane domain (TMD: pink) is followed by the RBPjκ association module (RAM) domain (purple), nuclear localization sequences (NLSs: blue), 7 ankyrin repeats (ANK) (light blue), and a transactivation domain containing a C-terminal proline/glutamic acid/serine threonine-rich motifs (PEST: gray). The major Notch ligands are also Type I membrane proteins that have an N-terminal Delta/Serrate/LAG-2 (DSL: light pink) domain and multiple EGF motifs (light blue). The ligands can be further classified based on the presence or absence of the Cysteine-rich (CR; purple) and of the Delta and OSM-11-like protein (DOS; lavender) domains. (b) Canonical Notch signaling pathway. Notch receptors are expressed at the plasma membrane as intramolecular heterodimers, held together by non-covalent interactions within the heterodimerization domain (HD). The receptors are activated by binding to ligands presented by a neighboring signal-sending cell. Ligand endocytosis is thought to generate the force needed to unfold the NRR (and perhaps dissociate the HD) to expose S2 to ADAM cleavage. Ectodomain shedding generates the membrane-anchored intermediate NEXT (Notch extracellular truncation), which is subsequently cleaved by γ-secretase progressively within the TMD to release the Notch intracellular domain (NICD) and the Nβ peptides. γ-secretase cleavage of Notch can occur at the cell surface or in an endosomal compartment. Once released, NICD translocates to the nucleus, associates with DNA-binding protein CSL and the transcriptional coactivator Mastermind to activate transcription. Some Notch ligands also go through sequential cleavages by ADAM proteases and γ-secretase. ADAM-mediated shedding of ligand ectodomains has been shown to modulate the strength and timing of Notch pathway activity. The role of the γ-secretase cleavage of ligands and released ligand intracellular domain fragments is still unclear. (c) TMD region of mouse Notch1, showing cleavage sites and products. Notch is cleaved by an ADAM protease at the S2 site. After ectodomain shedding, γ-secretase cleaves the Notch TMD, starting at the S3 site. Multiple scissile bonds can be cleaved to release different NICD molecules with varying N-terminal residues. Only NICD-V (blue) is resistant to N-end rule degradation and is likely the major biologically functional species. TMD proteolysis then proceeds toward S4 until the Nβ peptides can be released.

Figure 2

Notch signaling is utilized in multiple organs in the adult for cell renewal and tissue maintenance. (a) In the adult intestine, there are two types of adult intestinal stem cells (ISCs): Bmi+ quiescent and Lgr5+ proliferating ISCs (both in pink). They produce transit amplifying (TA) cells (light orange), and differentiate into four types of cells: absorptive enterocyte (light blue), secretory goblet (green), enteroendocrine (blue), and Paneth (purple) cells. Notch signaling promotes (blue arrow) proliferation of the adult ISCs and determines binary cell fate decisions between absorptive and secretory cells. (b) During adult hematopoiesis, Notch signaling promotes T cell lineage differentiation and regulates multiple other differentiation steps. It is still controversial whether Notch signaling regulates proliferation of hematopoietic stem cells (HSCs: pink) in the adult. Leukemia/lymphoma related factor (LRF) is a negative regulator of Notch signaling in the bone marrow. (c) In the adult skin, Notch signaling promotes spinous cell fate. Ablation of Notch signaling leads to tumorigenesis through non-cell autonomous effects. It also leads to secretion of thymic stromal lymphopoietin (TSLP), which can eventually lead to atopic dermatitis and asthma in the adult. (d) Adult neurogenesis takes place in two regions of the brain, the subgranular zone (SGZ) of the hippocampus and the subventicular zone (SVZ). In the SVZ, Notch signaling promotes cell proliferation in the adult neural stem cells (NSCs, pink, marked by glial fibrillary acidic protein (GFAP), glutamate-aspartate transporter (GLAST), or Nestin) and inhibits differentiation toward transit amplifying (TA) cells (light blue). Notch signaling maintains quiescence of ependymal cells (ciliated cells), which produce astrocyte (pink) and neuroblast (blue) upon stroke/injury. In the SGZ, Notch signaling promotes proliferation of adult NSCs (pink) and inhibits entry from NSCs to TA cells and/or cell cycle exit. Notch signaling could also promote survival and maturation of neurons and modulate neuritogenesis in mature neurons. (e) In adult muscle, Notch signaling is activated upon injury in satellite cells (light blue), which are the adult muscle stem cells, and promotes proliferation to produce myogenic progenitors (pink). Asymmetric localization of Notch inhibitor Numb during cell divisions results in two daughter cells: myoblast (blue) and a myogenic progenitor.