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Hypertrophy, hyperplasia and altered mucus secretion from the respiratory submucosal glands (SMG) are characteristics of airway diseases such as cystic fibrosis, asthma and chronic bronchitis. More commonly, hyper-secretion of the nasal SMGs contributes to allergic rhinitis and upper airway infection. Considering the role of these glands in disease states, there is a significant dearth in understanding the molecular signals that regulate SMG development and patterning. Due to the imperative role of FGF signalling during the development of other branched structures, we investigated the role of Fgf10 during initiation and branching morphogenesis of murine nasal SMGs. Fgf10 is expressed in the mesenchyme around developing SMGs while expression of its receptor Fgfr2 is seen within glandular epithelial cells. In the Fgf10 null embryo, Steno's gland and the maxillary sinus gland were completely absent while other neighbouring nasal glands showed normal duct elongation but defective branching. Interestingly, the medial nasal glands were present in Fgf10 homozygotes but missing in Fgfr2b mutants, with expression of Fgf7 specifically expressed around these developing glands, indicating that Fgf7 might compensate for loss of Fgf10 in this group of glands. Intriguingly the lateral nasal glands were only mildly affected by loss of FGF signalling, while these glands were missing in Eda mutant mice, where the Steno's and maxillary sinus gland developed as normal. This analysis reveals that regulation of nasal gland development is complex with different subsets of glands being regulated by different signalling pathways. This analysis helps shed light on the nasal gland defects observed in patients with hypohidrotic ectodermal dysplasia (HED) (defect EDA pathway) and LADD syndrome (defect FGFR2b pathway)., Highlights • Murine nasal submucosal glands express Fgf10, Fgfr2 and EDA during embryonic development. • All nasal glands require FGF10 for branching morphogenesis. • FGF10 is required for gland budding and ductal morphogenesis of the Steno's gland and the maxillary sinus glands. • EDA signalling is essential for Lateral Nasal Gland and Medial Nasal Gland budding and ductal morphogenesis.

During the formation of repetitive ectodermally derived organs such as mammary glands, lateral line and teeth, the tissue primordium iteratively initiates new structures. In the case of successional molar development, new teeth appear sequentially in the posterior region of the jaw from Sox2+ cells in association with the posterior aspect of a pre-existing tooth. The sequence of molar development is well known, however, the epithelial topography involved in the formation of a new tooth is unclear. Here, we have examined the morphology of the molar dental epithelium and its development at different stages in the mouse in vivo and in molar explants. Using regional lineage tracing we show that within the posterior tail of the first molar the primordium for the second and third molar are organized in a row, with the tail remaining in connection with the surface, where a furrow is observed. The morphology and Sox2 expression of the tail retains characteristics reminiscent of the earlier stages of tooth development, such that position along the A-P axes of the tail correlates with different temporal stages. Sox9, a stem/progenitor cell marker in other organs, is expressed mainly in the suprabasal epithelium complementary with Sox2 expression. This Sox2 and Sox9 expressing molar tail contains actively proliferating cells with mitosis following an apico-basal direction. Snail2, a transcription factor implicated in cell migration, is expressed at high levels in the tip of the molar tail while E-cadherin and laminin are decreased. In conclusion, our studies propose a model in which the epithelium of the molar tail can grow by posterior movement of epithelial cells followed by infolding and stratification involving a population of Sox2+/Sox9+ cells., Summary: This study proposes a model for repetitive tooth formation in which the epithelium can grow by the movement of epithelial cells followed by infolding and stratification of Sox2/Sox9 positive cells.