However, due to the limitations of using experimental models, the mechanism of adult mouse SMG tissue morphogenesis, including lumen formation, has remained elusive. RA has been reported to be an essential factor in the initial stages of embryonic development of SMGs in the salivary glands ( Wright et al., 2015 Abashev et al., 2017 Metzler et al., 2018). RAR or RXR isoforms have redundant roles, enabling them to compensate for each other under specific conditions. RA-mediated signaling activates its nuclear receptors, including the retinoic acid receptor (RAR) family and retinoid X receptor (RXR) family transcription factors. RA has several roles in organ morphogenesis, embryonic development, immune system, and growth of various cell types ( Tanumihardjo, 2011). Retinoids are a group of nutritional compounds that include retinol, retinal, and retinoic acid (RA). Several factors, including the fibroblast growth factor (FGF) family, epidermal growth factor (EGF) family, Wnt pathway components, bone morphogenetic proteins (BMPs), neurotrophic growth factor family, and neurotransmitter signaling components, are involved in the tightly regulated salivary gland development in a spatiotemporal manner ( De Moerlooze et al., 2000 Miyazaki et al., 2004 Jaskoll et al., 2005 Knox et al., 2010 Patel et al., 2011 Mattingly et al., 2015). The process of duct formation encompasses duct elongation, fusion of microlumens to form contiguous large lumen, and lumen expansion during development stages ( Nedvetsky et al., 2014). Murine salivary glands, particularly submandibular glands (SMGs), have been widely used as a model for studying salivary gland development and common processes in branching morphogenesis and tubulogenesis ( Steinberg et al., 2005 Nitta et al., 2009 Hsu and Yamada, 2010 Knox et al., 2010 Nedvetsky et al., 2014).
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