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

Alison J May,Denis Headon,David P Rice,Alistair Noble,Abigail S Tucker

doi:10.1016/j.ydbio.2016.08.030

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).

Highlights

Glands, gives rise to chronic rhinosinusitis and infection of the upper airway tract (Peña et al, 2007; Wu et al, 2011)
During gland branching at E16.5 (Fig. 2D), Fgf10 expression was apparent throughout the mesenchyme surrounding the end buds of the Steno's gland (Fig. 2E), while Fgfr2 mRNA was evident within the epithelial cells of the gland buds (Fig. 2F)
Fgf10 was expressed throughout the mesenchyme adjacent to the maxillary sinus gland (MSG) primordium at E14.5 (Fig. 2G and H), with Fgfr2 expression observed within the maxillary sinus epithelium from which the MSG buds (Fig. 2I)

Summary

Introduction

Glands, gives rise to chronic rhinosinusitis and infection of the upper airway tract (Peña et al, 2007; Wu et al, 2011). Considering this significant involvement of SMGs in pulmonary diseases, research is lacking in the mechanisms modulating gland development and homeostasis. Members of the fibroblast growth factor (FGFs) family of polypeptide proteins have been shown to be involved in branching morphogenesis of other organs such as the lung, salivary and lacrimal glands. A milder form of this disease, known as Aplasia of Lacrimal and Salivary Glands (ALSG) (OMIM 180920), gives rise to the same symptoms as LADD, most often including xerothalmia (dryness of the eye) and xerostomia (dry mouth) (Wiedemann, 1997; Milunsky et al, 1990)

Methods

Results

Conclusion