Notch Signaling and the Developing Skeleton

Abstract

Notch signaling is an important regulator of skeletogenesis at multiple developmental stages. The Notch signaling pathway is involved in the promotion of somite segmentation, patterning and differentiation into sclerotome pre-chondrogenic cells to allow for appropriate axial skeleton development. In addition, studies performed in vitro and in vivo demonstrate that Notch signaling suppresses chondrogenic and osteoblastic differentiation and negatively regulates osteoclast formation and proliferation. Through the use of in vitro and in vivo approaches, Notch signaling has been shown to regulate somitogenesis, chondrogenesis, osteoblastogenesis and osteoclastogenesis that ultimately affect skeletogenesis. Dysregulation of Notch signaling results in congenital skeletal malformations that could reveal therapeutic potential.

Microfibril-associated Glycoprotein 2 (MAGP2) Loss of Function Has Pleiotropic Effects in Vivo

“…Jagged1/Notch intracellular domain signaling also impedes osteoclast formation by inhibiting RANKL expression in mature osteoblasts (43). Inhibition of Notch signaling in the context of bone formation increases osteoblast differentiation, thereby increasing bone formation (43). The studies detailed here indicate that loss of MAGP2 alone has a slight net anabolic effect on bone mass.…”

“…MAGP2, however, has the added ability to activate Notch signaling through release of Jagged1 from the cell surface (42). The activated Notch intracellular domain inhibits osteoclast differentiation both from hematopoietic precursors and from preosteoclasts (43). Jagged1/Notch intracellular domain signaling also impedes osteoclast formation by inhibiting RANKL expression in mature osteoblasts (43).…”

“…The activated Notch intracellular domain inhibits osteoclast differentiation both from hematopoietic precursors and from preosteoclasts (43). Jagged1/Notch intracellular domain signaling also impedes osteoclast formation by inhibiting RANKL expression in mature osteoblasts (43). Inhibition of Notch signaling in the context of bone formation increases osteoblast differentiation, thereby increasing bone formation (43).…”

Enthesis regeneration: a role for Gli1+ progenitor cells

“…These cells could theoretically be activated to participate in repair and regeneration of the enthesis. To explore whether this small cell population had progenitor cell characteristics, immunostaining was performed for Notch1, an important stem cell regulator involved in skeletogenesis (Chen et al, 2014;Mead and Yutzey, 2012). In the mature enthesis, staining of Notch1 was limited to the small number of remaining Gli1+ cells (Fig.…”

An understanding of intervertebral disc development, maturation and cell phenotype provides clues to direct cell-based tissue regeneration therapies for disc degeneration

“…Although being mesoderm-derived, due to a process of mesenchymal-epithelial transition, the notochord and somites display epithelioid characteristics such as cell polarity and cell-cell contact [33]. The main functions of the notochord at this stage are to provide longitudinal support to the embryo, to direct the formation of the neural tube from the ectoderm-derived neural plate (neurulation) [34] and to induce paraxial mesoderm segmentation in pairs of cranio-caudally distributed somites (somitogenesis) [35].…”