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Abstract
Understanding the molecular regulation of taste organogenesis, which includes tongue, taste papillae, and taste buds, is crucial considering that developmental defects in the tongue and taste papillae, such as aglossia, macroglossia, microglossia, ankyloglossia, ageusia, dysgeusia, and hypogeusia can cause serious disease conditions such as muteness, taste-related disorders, and difficulties in food processing. Detailed information concerning molecular mechanisms governing tongue and taste papilla formation remains incomplete. Here, we demonstrate how neural crest (NC)-derived tongue mesenchyme regulates mesenchymal-epithelial interactions via Bone morphogenetic protein (BMP) and Neurofibromin 2 (Nf2) signaling pathways for the formation of tongue and taste papillae. To investigate the specific roles of BMP and Nf2 signaling pathways, we utilized NC and NC-derived specific Wnt1-Cre to constitutively activate ALK2 (caAlk2) and conditionally knock out Alk3 (Alk3 cKO) and Nf2 (Nf2 cKO) in a tongue mesenchyme-specific manner. We found that Type I BMP receptors ALK2 and ALK3 in the mesenchyme—the main determinants of the BMP signaling pathway—play distinct roles in tongue and taste papilla development. Dramatically smaller (microglossia) and misshapen tongues with progressively severe size reduction along the anteroposterior axis, absence of a pharyngeal region, and apparent changes in lingual tissues including the epithelium, muscle, and nerve fibers were observed in Wnt1-Cre/caAlk2 mutants, suggesting that ALK2-mediated BMP signaling in the mesenchyme is essential in orchestrating various tissues for the proper development of the tongue and its appendages in a region-specific manner. In contrast, Alk3 cKO in the tongue mesenchyme resulted in the complete absence of taste papilla placodes. Further analyses using RNA-Sequencing, Mass spectrometry combined with functional analyses using tongue organ cultures revealed that ALK3-mediated BMP signaling in the mesenchyme suppresses the secretion of inhibitory secretory proteins and promotes taste papilla development in the tongue epithelium. In Nf2 cKO mutants, distinct alterations of cell proliferation in a region-specific manner were detected, i.e., cell proliferation decreased anteriorly and increased posteriorly, leading to a tip-pointed and posteriorly widened tongue in the early developmental stages. However, in the later stages, Nf2 cKO mutants had significantly decreased cell proliferation throughout the entire tongue organ, suggesting a stage-specific role of Nf2 in regulating cell proliferation.