Notch regulation of bone development and remodeling and related skeletal disorders

Abstract

Notch signaling mediates cell-to-cell interactions that are critical for embryonic development and tissue renewal. In the canonical signaling pathway, the Notch receptor is cleaved following ligand binding, resulting in the release and nuclear translocation of the Notch intracellular domain (NICD). NICD induces gene expression by forming a ternary complex with the DNA binding protein CBF1/Rbp-Jk, Suppressor of Hairless, Lag1, and Mastermind-Like (Maml). Hairy Enhancer of Split (Hes) and Hes related with YRPW motif (Hey) are classic Notch targets. Notch canonical signaling plays a central role in skeletal development and bone remodeling by suppressing the differentiation of skeletal cells. The skeletal phenotype of mice misexpressing Hes1 phenocopies partially the effects of Notch misexpression, suggesting that Hey proteins mediate most of the skeletal effects of Notch. Dysregulation of Notch signaling is associated with diseases affecting human skeletal development, such as Alagille syndrome, brachydactyly and spondylocostal dysostosis. Somatic mutations in Notch receptors and ligands are found in tumors of the skeletal system. Overexpression of NOTCH1 is associated with osteosarcoma, and overexpression of NOTCH3 or JAGGED1 in breast cancer cells favors the formation of osteolytic bone metastasis. Activating mutations in NOTCH2 cause Hajdu-Cheney syndrome, which is characterized by skeletal defects and fractures, and JAG1 polymorphisms, are associated with variations in bone mineral density. In conclusion, Notch is a regulator of skeletal development and bone remodeling, and abnormal Notch signaling is associated with developmental and postnatal skeletal disorders.

Figure 1

Transactivation of Notch canonical signaling. Under unstimulated conditions, co-repressors of transcription are bound to Epstein-Barr virus latency C promoter binding factor (CBF)1 / Suppressor of Hairless / Lag1 (CSL)/ RBP-Jκ and recruit suppressors of transcription. Upon binding to Delta/Serrate/Lag-2 (DSL) ligands the Notch receptor is cleaved, resulting in the release of the Notch intracellular domain (NICD). The NICD translocates to the nucleus and forms a ternary complex with CSL and Mastermind-Like (MamL). This complex displaces the transcriptional co-repressors, resulting in recruitment of activator of transcription and expression of Notch target genes, such as Hairy Enhancer of Split (Hes) and Hes related with YRPW motif (Hey).