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Review
. 2010 Feb;30(4):886-96.
doi: 10.1128/MCB.01285-09. Epub 2009 Dec 7.

Notch and the skeleton

Stefano Zanotti  1 , Ernesto Canalis
Affiliations
Review

Notch and the skeleton

Stefano Zanotti et al. Mol Cell Biol. 2010 Feb.

Abstract

Notch receptors are transmembrane receptors that regulate cell fate decisions. There are four Notch receptors in mammals. Upon binding to members of the Delta and Jagged family of transmembrane proteins, Notch is cleaved and the Notch intracellular domain (NICD) is released. NICD then translocates to the nucleus, where it associates with the CBF-1, Suppressor of Hairless, and Lag-2 (CSL) and Mastermind-Like (MAML) proteins. This complex activates the transcription of Notch target genes, such as Hairy Enhancer of Split (Hes) and Hes-related with YRPF motif (Hey). Notch signaling is critical for the regulation of mesenchymal stem cell differentiation. Misexpression of Notch in skeletal tissue indicates a role as an inhibitor of skeletal development and postnatal bone formation. Overexpression of Notch inhibits endochondral bone formation and osteoblastic differentiation, causing severe osteopenia. Conditional inactivation of Notch in the skeleton causes an increase in cancellous bone volume and enhanced osteoblastic differentiation. Notch ligands are expressed in the hematopoietic stem cell niche and are critical for the regulation of hematopoietic stem cell self-renewal. Dysregulation of Notch signaling is the underlying cause of diseases affecting the skeletal tissue, including Alagille syndrome, spondylocostal dysostosis, and possibly, osteosarcoma.

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Figures

FIG. 1.
FIG. 1.
Domain organization of the four mammalian Notch receptors. Abbreviations: ANK (ankyrin domains), EGF (epidermal growth factor-like), HD (heterodimerization domain), NLS (nuclear localization sequence), PEST (proline-, glutamic acid-, serine-, and threonine-rich domain), RAM (Rbp-Jk association module), TD (transmembrane domain). The number of EFG repeats is 36 in Notch1 and Notch2, 34 in Notch3, and 29 in Notch4. The dotted lines represent interactions between the 2 halves of the Notch heterodimer; the yellow segment represents an additional NLS.
FIG. 2.
FIG. 2.
Domain organization of the Notch ligands. In the left panel (canonical ligands), abbreviations are as follows: C (C-terminal region), CR (cysteine-rich domain), DOS (Delta and OSM-11-like proteins), DSL (Delta/Serrate/Lag2 motif), EGF (epidermal growth factor-like repeat), N (N-terminal signal), and TD (transmembrane domain). In the right panel (noncanonical ligands), abbreviations are as follows: CT (cysteine knot domain), FNIII (fibronectin type III domain), GPI (glycosylphosphatidylinositol anchor), IgCAM (immunoglobulin-containing cell adhesion molecule domain), IGFBP (insulin-like growth factor binding protein domain), MBD (matrix binding domain), Q (glutamine-rich region), RGD (integrin binding motif), TSP1 (thrombospondin1-like domain), and VWF (Von Willebrand factor type-C-like domain).
FIG. 3.
FIG. 3.
Activation of transcription by the Notch intracellular domain (NICD). Under basal, unstimulated conditions, corepressors of transcription are bound to Epstein-Barr virus latency C promoter binding factor 1, Suppressor of Hairless, and Lag1 (CSL) and recruit histone deacetylase (HDAC) to suppress transcription. Following translocation of NICD (see Fig. 1 for domain organization) to the nucleus, a ternary complex composed of NICD, CSL, and Mastermind-Like (MAML) is formed. This complex displaces the corepressors and HDAC, resulting in recruitment of CBP/p300, acetylation (Ac) of histones, and gene expression.
FIG. 4.
FIG. 4.
The diagram represents the effects of Notch in the skeleton. CSL (Epstein-Barr virus latency C promoter binding factor 1, Suppressor of Hairless, and Lag1) indicates involvement of the canonical Notch signaling pathway. Notch suppresses chondrocyte proliferation and differentiation during the formation of the hyaline cartilage and inhibits hypertrophic differentiation. Notch inhibits osteoblast differentiation by interacting with β-catenin (β-Cat), Runt-related transcription factor-2 (Runx-2), and Osterix (Osx). Notch suppresses osteoclastogenesis directly in mononuclear precursors and indirectly by inducing osteoprotegerin (OPG) expression and, as a consequence, suppresses bone remodeling. Notch signaling sustains hematopoietic stem cell self-renewal.
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