Canonical Wnt signaling regulates branching morphogenesis of submandibular gland by modulating levels of lama5

Abstract

Background: Branching morphogenesis is a crucial developmental mechanism for the formation of a typical bush-like structure of the submandibular gland (SMG). However, the detailed mechanism underlying this process remains to be fully understood. Here, we investigate whether a cross-talking may exist between Wnt/beta-catenin signaling pathway and lama5 during the branching process in SMG development. Methods: Embryonic mouse SMG organ culture model was established, and the validity of this model was confirmed. The roles of Wnt/beta-catenin signaling pathway, FGF signaling, and Lama5 in the branching process were investigated by morphogenesis assays. And the interactions between these signaling were also investigated and demonstrated by morphogenesis assays and gene expression patterns. Results: We demonstrated that E12 or E13 SMG organ culture model can be used as an ideal approach to study the process of branching morphogenesis. And branching morphogenesis assay revealed that the epithelial branching process would be promoted when the canonical Wnt pathway was inhibited and be significantly suppressed when wnt pathway is over activated. Further experiments indicated that FGF signaling acts most likely acts upstream as a negative regulator of the canonical Wnt pathway during the branching process, whose effect could be partially reversed by Wnt3a. And we further demonstrated that Wnt/beta-catenin signaling regulates the branching morphogenesis through Lama5. Conclusion: Our present work demonstrated that Wnt/beta-catenin signaling pathway acting downstream of FGF signaling may serve as a negative regulatory mechanism in the process of SMG branching morphogenesis through Lama5.

MEIS-WNT5A axis regulates development of fourth ventricle choroid plexus

“…Canonical and non-canonical WNT pathways have been implicated in regulating different aspects of epithelial morphogenesis, such as apical constriction, which is crucial for inducing branching in epithelial monolayers (Choi and Sokol, 2009;Fumoto et al, 2017). The striking difference observed between mouse LV and 4V ChP morphologies, together with distinct activation of WNT pathway signaling, raises the possibility that tight regulation of canonical versus non-canonical WNT signaling contributes to induction or modulation of epithelial folding, as has been recently proposed for developing Drosophila wing disc epithelium or in mouse embryonic submandibular gland (Gou et al, 2021;Sui and Dahmann, 2020). Although Wnt5a contributions to 4V ChP morphogenesis may be conserved, it is important to note that the process of ChP morphogenesis will likely prove to involve multiple pathways, as human LV ChP, in contrast to rodent LV ChP, exhibits a branched structure.…”

Development of high-throughput lacrimal gland organoid platforms for drug discovery in dry eye disease

“…In summary, the mesenchymal BMP7 signals can regulate LG branching morphogenesis by promoting mesenchymal proliferation/condensation and epithelial proliferation/elongation. It has been proposed that such mechanisms are suppressed by canonical Wnt signaling in the periorbital mesenchyme [58] .…”

ΔNp63 regulates Sfrp1 expression to direct salivary gland branching morphogenesis

“…Wnt signals are also critical for salivary gland morphogenesis where it is initially localized to the mesenchyme at E12 and by E13.5, it is expressed in the ductal cells where it is has been shown to play important roles in ductal differentiation. Indeed, during the early stages of salivary gland development, studies have revealed that inhibition of Wnt signaling is required for branching morphogenesis [ 10 , 11 ]. Similarly, studies in the lung and lacrimal gland support these findings [ 12 ].…”