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WIREs Dev Biol
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Salivary gland development and disease

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Abstract Mammalian salivary glands synthesize and secrete saliva via a vast interconnected network of epithelial tubes attached to secretory end units. The extensive morphogenesis required to establish this organ is dependent on interactions between multiple cell types (epithelial, mesenchymal, endothelial, and neuronal) and the engagement of a wide range of signaling pathways. Here we describe critical regulators of salivary gland development and discuss how mutations in these impact human organogenesis. In particular, we explore the genetic contribution of growth factor pathways, nerve‐derived factors and extracellular matrix molecules to salivary gland formation in mice and humans. WIREs Dev Biol 2015, 4:573–590. doi: 10.1002/wdev.194 This article is categorized under: Signaling Pathways > Global Signaling Mechanisms Vertebrate Organogenesis > From a Tubular Primordium: Branched Birth Defects > Organ Anomalies
Mouse and human salivary glands develop through the process of branching morphogenesis. Schematic (a) and histological (b) representations of SG development. (b) Mouse and human SG development. Human development is measured in weeks and mouse development in days. E = embryonic day. (Reprinted with permission from Ref . Copyright 2010 John Wiley and Sons)
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Developmental processes, cell interactions, and signaling pathways involved in salivary gland organogenesis.
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GFRa2 localizes to the nerves and neurturin (NRTN) to the acinar cells of developing salivary glands and NRTN promotes axon outgrowth from parasympathetic ganglia. (a) E13.5 SG labeled with GFRa2 and peanut agglutinin (epithelial marker). (b) Post‐natal day 1 SG immunostained for neurturin, acinar cell cytoskeleton (F‐actin, red) and neurons (blue). (c) E13 parasympathetic ganglia cultured with NRTN for 48 h shows extensive outgrowth. (d) Left panel: Bidirectional communication between parasympathetic nerves and the SG epithelial progenitor cells. NRTN from epithelium (pink) promotes innervation and increases production of acetylcholine (ACh), which in turn maintains KRT5+ basal progenitor cells. Right panel: NRTN is synthesized by cKIT+ progenitor cells in the end buds.
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Differential gene expression in the developing SG. Expression of Egf (a), Hh (b), and Bmp (c) family members in epithelial and mesenchymal compartments of the SG at embryonic day 13. Expression patterns were derived from a pre‐existing microarray database available online (http://sgmap.nidcr.nih.gov/sgmap/sgexp.html). Data are presented as a percentage of total expression (epithelium + mesenchyme) of the SG.
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Dysregulation of FGF signaling results in aberrant branching morphogenesis. (a) E13 SGs [wild type and SG deficient in the Sprouty (Spry1) genes 1 and 2] were cultured for 24 h in the presence or absence of recombinant FGFR2b‐Fc (10 µg/mL). Epithelium was immunostained for E‐cadherin. (b) Left panel: FGF signaling regulates progenitor cells, and epithelial branching. Right panel: Increased FGF signaling [e.g., overexpression of FGF7 in the epithelium or ablation of negative regulators of FGF signaling (Spry1 and 2) in vivo] reduces SG growth, delays differentiation and impairs gangliogenesis. Epithelium is labeled pink, mesenchyme brown.
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Signaling Pathways > Global Signaling Mechanisms
Birth Defects > Organ Anomalies
Vertebrate Organogenesis > From a Tubular Primordium: Branched