FGF and EDA pathways control initiation and branching of distinct subsets of developing nasal glands

Abstract

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).

FGF10 is an essential regulator of tracheal submucosal gland morphogenesis

“…As previously reported in other glands (May et al 2016;Chatzeli et al 2017), here we show that Fgf10 is expressed in the tracheal mesenchyme adjacent to the gland epithelium during branching morphogenesis at P7. Due to agenesis of the lungs, Fgf10 -/-mice die at birth (Sekine et al 1999;Min et al 1998), thereby preventing the study of later stages of tracheal gland development in the null mutant.…”

“…Furthermore, we previously showed that Fgf10 expression is essential for a subset of nasal glands, with other Fgfs compensating for the loss of Fgf10 in some glands (May et al 2016). The lateral nasal glands, for example, only require Fgf10 for later gland branching stages, while the Steno's gland and the sinus glands require Fgf10 expression earlier at gland initiation stages (May et al 2016). The SMGs therefore show a reliance on FGF10 signalling more similar to the stenos and sinus glands.…”

Bones, Glands, Ears and More: The Multiple Roles of FGF10 in Craniofacial Development

“…Multiple FGFs can activate both FGFR2 IIIb (FGF3, 7, and 22 from the Fgf7 subfamily; but also FGF1) and FGFR2 IIIc (e.g., FGF1, 2, 4, 5, 6, 8, 9, or 16) ( Zhang et al, 2006 ). Nevertheless, the Fgf10 and Fgfr2 null mice share the majority of defects within the orofacial area, with the exception of milder tooth and inner ear defects in Fgf10 mutant mice ( Kettunen et al, 2000 ; Ohuchi et al, 2000 ; Pirvola et al, 2000 ), and development of medial nasal glands, which are absent in Fgfr2 null mutants but form normally in Fgf10 null mice ( May et al, 2016 ). The milder phenotypes in Fgf10 mutants are mostly explained by compensation by FGF3 ( Kettunen et al, 2000 ; Wright, 2003 ) or FGF7 ( May et al, 2016 ).…”

“…The proteoglycans at the cell surface and in the extracellular matrix also affect lacrimal gland morphogenesis – the O -sulfation of heparan sulfate was shown to be essential for FGF10–FGFR2 interaction on lacrimal gland cell surface ( Qu et al, 2011 ). In addition to the large orofacial glands, FGF10 also plays an important role during development of nasal submucosal glands responsible for mucus secretion in airways ( May et al, 2016 ).…”

Orientation of the Mitotic Spindle in the Development of Tubular Organs

“…As a result of this process, most tubular organs of the circulatory and urogenital system are derived from the mesoderm. In contrast, tubular digestive organs, and respiratory organs or glands are formed by differentiation of the endoderm [Piliszek et al, 2016], and include the pharynx [Liberty et al, 2013], stomach [Kim and Shivdasani, 2016], intestines [Roulis and Flavell, 2016], trachea and bronchus [Turcatel et al, 2013], and some glandular ducts [Huang et al, 2014;May et al, 2016].…”