Invited Commentary on: Role of Notch Signaling in the Physiological Patterning of Posterofrontal and Sagittal Cranial Sutures
In humans, Alagille syndrome, an autosomal-dominant disease caused by mutations in the Jagged1 gene, has been shown to be associated with unilateral coronal craniosynostosis.6 Mutations in Jagged1 have been identified in approximately 80% of patients with Alagille syndrome.
Findings gained from the study presented herein by Dr Liu et al7 revealed a differential temporal profile of Notch signaling between the fusing PF and nonfusing SAG sutures. Gene expression profile of notch ligands, receptors, and target genes performed at different time points corresponding to the window of PF suture fusion process would suggest that Notch signaling decreases over-time in the PF suture, whereas it increases in the SAG suture. This is an interesting finding sharing similarity with what previously observed for the activation profile of canonical Wnt signaling in cranial sutures. An earlier study by Behr et al7 reported that, similarly to Notch signaling, cWnt signaling activation decreases significantly in PF suture undergoing fusion through endochondral ossification. In contrast, cWnt signaling remains sustained in the SAG patent suture as well as in other cranial patent sutures such as coronal (COR) and lamboid (LAM). This similarity (parallelism) raises several important questions: do these 2 signaling pathways cross-talk? And if so, what is their hierarchical status? Which one of the 2 signaling is upstream and controls the other one? How Notch and cWnt signaling pathways relate and integrate in the context of cranial suture pattern/ development is indeed, an appealing investigation to be pursued.
In their study, Dr Liu et al7 also demonstrated that activation of Notch signaling induces proliferation of calvarial osteoblast cells while inhibiting their differentiation. By performing a proliferation assay in the presence of exogenously added recombinant Jagged1 protein, there was a significant increase in proliferation and decrease of endogenous expression of the osteogenic markers Col1a, Alkaline Phosphatase, and Osteocalcin as compared to untreated cells. Conversely, treatment with the Notch signaling inhibitor DAPT decreased proliferation of osteoblast cells while increasing the expression of osteogenic markers. This observation sheds light on the potential role of activated Notch signaling in controlling suture patency as previously demonstrated for cWnt signaling8 and sets the stage for potential therapeutic intervention in Alagille and perhaps other craniosynostosis as well.
Notch signaling has been shown over the past few years to play an important role in stem cells as a crucial regulator of their behavior.9,10 Several studies revealed that the Notch signaling plays varied and critical roles in lineage-specific differentiation of pluripotent embryonic stem cells, and in controlling stem cell numbers and activity in the context of age-related tissue degeneration, injury-induced tissue repair, and cancer.