Intracellular signaling cascades activated by growth factors and integrins are known to drive development and differentiation in several tissues. Nevertheless, no information is available about such mechanisms in developing salivary glands. The earlier published and preliminary data show that engagement of both the epidermal growth factor receptor (EGFR) and integrins containing the alpha6-subunit are needed for branching morphogenesis of the fetal mouse submandibular gland (SMG). Several intracellular pathways activated by EGFR and/or integrins have been defined. The best characterized pathways signal via the RAS/MEK/ERK cascade, or phospholipase Cgamma1 (PLCgamma1), or phosphoinositol-3-kinase (PI3K). The latter two enzymes activate protein kinase C (PKC). The preliminary studies have already shown that the RAS/MEK/ERK pathway is necessary for branching morphogenesis of the SMG, and that its activity varies with fetal age. A system for analysis of branching morphogenesis of isolated fetal SMG epithelium cultured under fully defined conditions with Matrigel and know amounts of EGF has recently become available. The Major Hypothesis is that age-dependent variations in the activity of the three major signaling pathways triggered by EGFR and by integrins affect the course of development of the SMG by a dynamic regulatory circuit of positive signaling by ERK and PKB, balanced by negative signaling by PKC. There are plans to test this hypothesis by:
Specific Aim 1 : To establish that various PKC negatively regulate the EGFR in the fetal SMG.
Specific Aim 2 : To demonstrate that signaling via PLCgamma1 and PI3K have essential roles in branching morphogenesis.
Specific Aim 3 : To identify the PKC isozymes that regulates branching morphogenesis.
Specific Aim 4 : To define the regulatory roles of the EGFR and of the alpha6-containing integrins on specific signaling components controlling branching morphogenesis of the SMG. The proposed studies will have significance for understanding normal developmental mechanisms, for defining dysfunction leading to congenital malformations or to transformations resulting in carcinomas, and for advancing efforts on regeneration and tissue engineering of salivary glands.
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