FGF10 is an essential regulator of tracheal submucosal gland morphogenesis

Abstract

Mucus secretion and mucociliary clearance are crucial processes required to maintain pulmonary homeostasis. In the trachea and nasal passages, mucus is secreted by submucosal glands (SMGs) that line the airway, with an additional contribution from goblet cells of the surface airway epithelium. The SMG mucus is rich in mucins and antimicrobial enzymes. Defective tracheal SMGs contribute to hyper-secretory respiratory diseases, such as cystic fibrosis, asthma, and chronic obstructive pulmonary disease, however little is known about the signals that regulate their morphogenesis and patterning. Here, we show that Fgf10 is essential for the normal development of murine tracheal SMGs, with gland development arresting at the early bud stage in the absence of FGF10 signalling. As Fgf10 knockout mice are lethal at birth, inducible knockdown of Fgf10 at late embryonic stages was used to follow postnatal gland formation, confirming the essential role of FGF10 in SMG development. In heterozygous Fgf10 mice the tracheal glands formed but with altered morphology and restricted distribution. The reduction in SMG branching in Fgf10 heterozygous mice was not rescued with time and resulted in a reduction in overall tracheal mucus secretion. Fgf10 is therefore a key signal in SMG development, influencing both the number of glands and extent of branching morphogenesis, and is likely, therefore, to play a role in aspects of SMG-dependent respiratory health.

New developments in the biology of fibroblast growth factors

“…Submucosal glands that line the airway produce mucus in the tracheal and nasal airways. Conditional knockout studies show that Fgf10 is required for submucosal gland development, regulating the number of glands and extent of epithelial branching (May et al, 2019).…”

FGF signaling regulates salivary gland branching morphogenesis by modulating cell adhesion

“…Our current understanding implicates FGF signaling primarily in mesenchymal-epithelial interactions (Chatzeli et al, 2017;Makarenkova et al, 2009;Sakakura et al, 1976;Steinberg et al, 2005;Wei et al, 2007). Fgf10 −/− mutants exhibit branching defects in multiple exocrine organs (Hoffman et al, 2002;Jaskoll et al, 2005;Mailleux et al, 2002;Makarenkova et al, 2000;May et al, 2016May et al, , 2019Ohuchi et al, 2000). Fgf8 hypomorphic mutants also exhibit SMG hypoplasia (Jaskoll et al, 2004).…”

Sci-Seq of Human Fetal Salivary Tissue Introduces Human Transcriptional Paradigms and a Novel Cell Population

“…General exocrine gland development shares a complex stepwise process including epithelial ingrowth to form a bud, branching morphogenesis and ductal elongation, and further, secretory cell differentiation (1). It has been well established that epithelial-mesenchymal interactions (2-6), integrin- (7,8) and fibroblast growth factor 10 (FGF10)-signaling are critical for exocrine gland morphogenesis and development (9)(10)(11)(12)(13)(14). However, the mechanism of action of signaling pathways and specific transcription factors that drive cell fate decisions during different exocrine gland development have remained largely elusive.…”