Alagille Syndrome (ALGS), an autosomal dominant genetic disorder characterized by liver choleostasis, low bone mass and poor fracture healing, is associated with mutations in Jagged-1 (JAG1),1 a gene that encodes a single transmembrane glycoprotein expressed in mammalian cell membranes, where it acts as a Notch ligand receptor. In an effort to explain why Jag1 mutations lead to the morbidity observed, Zhu et al. conducted in vitro studies using primary mouse and human mesenchymal stem cells (MSCs) to determine the impact of Jag1-activated Notch signaling on osteoblastogenesis.2
Overall, the results suggested that Jag1 acts through canonical Notch signaling in association with PKCδ signaling to stimulate differentiation of osteoblasts. Some discrepancies were noted in the effect that Jag1 had on mouse MSCs (mMSCs) and human MSCs (hMSCs); plating hMSCs on Jag1 leads to the induction of osteoblast differentiation but the same experiment using mMSCs caused inhibition of osteoblastogenesis.
Editor's comment: The observation that Jag1 causes release of the Notch-2 intracellular domain, which then interacts with Jag1-activated PKCδ to induce MSCs to differentiate into osteoblasts, provides a possible explanation for the genetic basis of ALGS. The study also highlights differences in murine and human MSCs, something that research into ALGS etiology should take into account.
References
- Kung AWC, Xiao S-M, Cherny S, Li GH, Gao Y, Tso G et al. Association of JAG1 with bone mineral density and osteoporotic fractures: a genome-wide association study and follow-up replication studies. Am J Hum Genet 2010;86:229–239. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhu F, Sweetwyne MT, Hankenson KD. PKCδ is required forJagged-1 induction of hMSC osteogenic differentiation. Stem Cells 2013; e-pub ahead of print 13 February 2013; 10.1002/stem.1353. [Google Scholar]
