Submandibular gland morphogenesis: Stage-specific expression of TGF-?/EGF, IGF, TGF-?, TNF, and IL-6 signal transduction in normal embryonic mice and the phenotypic effects of TGF-?2, TGF-?3, and EGF-r null mutations

Abstract

Branching morphogenesis of the mouse submandibular gland (SMG) is dependent on cell-cell conversations between and within epithelium and mesenchyme. Such conversations are typically mediated in other branching organs (lung, mammary glands, etc.) by hormones, growth factors, cytokines, and the like in such a way as to translate endocrine, autocrine, and paracrine signals into specific gene responses regulating cell division, apoptosis, and histodifferentiation. We report here the protein expression in embryonic SMGs of four signal transduction pathways: TGF-␣/EGF/EGF-R; IGF-II/IGF-IR/IGF-IIR; TGF-␤s and cognate receptors; TNF, IL-6, and cognate receptors. Their in vivo spatiotemporal expression is correlated with specific stages of progressive SMG development and particular patterns of cell proliferation, apoptosis, and mucin expression. Functional necessity regarding several of these pathways was assessed in mice with relevant null mutations (TGF-␤2, TGF-␤ 3 , EGF-R). Among many observations, the following seem of particular importance: (1) TGF-␣ and EGF-R, but not EGF, are found in the Initial and Pseudoglandular Stages of SMG development; (2) ductal and presumptive acini lumena formation was associated with apoptosis and TNF/TNF-R1 signalling; (3) TGF-␤2 and TGF-␤3 null mice have normal SMG phenotypes, suggesting the presence of other pathways of mitostasis; (4) EGF-R null mice displayed an abnormal SMG phenotype consisting of decreased branching. These and other findings provide insight into the design of future functional studies. Anat Rec 256: 252-268, 1999. 1999 Wiley-Liss, Inc.

Estrogen and Insulin Replacement Therapy Modulates the Expression of Insulin‐Like Growth Factor‐I Receptors in the Salivary Glands of Diabetic Mice

“…These IGF actions can have also relation with autocrine, paracrine, and with endocrine regulatory mechanisms in different tissues (Pavelić et al, 2007;Vitale et al, 2009). Likewise, also the salivary glands are dependent on factors of growth and endocrine, autocrine, and paracrine signals, which regulate the cell division, apoptosis, and histodifferentiation (Jaskoll and Melnick, 1999). Similar to what was observed in the present study, where the autocrine and paracrine signals also can be involved in the attempt of tissue recovery.…”

FGFR2b signaling regulates ex vivo submandibular gland epithelial cell proliferation and branching morphogenesis

“…However, media with 10% horse serum was used in these experiments, which contains mitogenic growth factors and makes comparison difficult with our serum-free conditions. The EGFR-null mouse (Jaskoll and Melnick, 1999) has macroscopically normal glands with a reduction of buds/area, suggesting that EGFR regulates SMG branch number in vivo but is not essential for SMG initiation or early branching. An exogenous EGFR ligand is not required for epithelial branching; however, the ECM may contain EGFR ligands or the epithelium may produce an endogenous EGFR ligand.…”

IL-6 Is Constitutively Expressed During Lung Morphogenesis and Enhances Fetal Lung Explant Branching

“…In adults, epithelial expression was also observed in other branching organs such as salivary glands (30), prostate (8,9), and mammary gland (7). However, IL-6 expression in fetuses was only described during submandibular gland morphogenesis (5,6). In fact, Melnick et al (5) showed a significant increase in IL-6 mRNA with progressive salivary gland development.…”

“…Several studies have emphasized the importance of IL-6 signaling in several processes of branching organs such as embryonic submandibular gland development (5,6), mammary gland remodeling (7), benign and malign prostate growth (8,9), and lung maturation (10).…”