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

Branching morphogenesis of the mouse submandibular gland (SMG) is dependent on cell-cell conversations between and within epithelium and mesenchyme. S uch conversations are typically mediated in other branching organs (lung, m ammary glands, etc,) by hormones, growth factors, cytokines, and the like i n such a way as to translate endocrine, autocrine, and paracrine signals in to specific gene responson, We repores regulating cell division, apoptosis, and histodifferentiatit here the protein expression in embryonic SMGs of f our signal transduction pathways: TGF-alpha/EGF/EGF-R; IGF-II/GF-IR/IGF-IIR ; TGF-beta s and cognate receptors; TNF, IL-6, and cognate receptors. Their in vivo spatiotemporal expression is correlated with specific stages of pr ogressive SMG development and particular patterns of cell, proliferation, a poptosis, and: mucin expression. Functional necessity regarding several of these pathways was assessed in mice with relevant null mutations (TGF-beta 2, TGF-beta(3), EGF-R). Among many observations, the following seem of part icular importance: (1) TGF-alpha and EGF-R, but not EGF, are found in the I nitial and Pseudoglandular Stages of SMG development; (2) ductal and presum ptive acini lumena formation was associated with apoptosis and TNF/TNF-R1 s ignalling; (3) TGF-beta 2 ana TGF-beta 3 null mice have normal SMG phenotyp es, 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 functi onal studies. Anat Rec 256:252-268, 1999. (C) 1999 Wiley-Liss, Inc.