Craniofacial Developmental Dynamics

National Institute Of Dental & Craniofacial Research

Investigators

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Abstract

This project is focused primarily on determining mechanisms of morphogenesis and maintenance of salivary glands and other organs. We are addressing the following major questions: 1. How do embryonic salivary glands and other branched organs generate their characteristic branched architectures during the process of branching morphogenesis? Specifically, how is the formation of clefts, buds, and ducts mediated and coordinated at molecular and biophysical levels? How can we facilitate bioengineering for organ replacement - particularly of salivary glands - by understanding branching morphogenesis and by promoting specific steps of this process? 2. What are the contributions of selective, local regulation of organ-specific gene expression, cell adhesion, embryonic cell sorting, extracellular matrix, integrins, signal transduction, and local cell migration to organ branching morphogenesis and organ specification? Branching morphogenesis of developing organs requires coordinated but still relatively incompletely understood changes in gene expression, epithelial cell-cell adhesion, cell-matrix adhesion, and cell motility. We had previously performed single-cell and bulk RNA transcriptomic analyses on embryonic submandibular versus parotid salivary glands to characterize their molecular identities at the very early stage of bud initiation. A key finding was the surprising degree of differences in gene expression patterns between these glands quite early in development, indicating gland specificity at even this early single-bud stage. Mesenchymal cells formed separate, well-defined clusters specific to each gland. For example, there were substantial differences between molecular markers and tissue localization of neuronal and muscle-related cells between these two glands. There were both distinct and overlapping patterns of gene expression in the epithelial cells of these two glands. In preliminary studies, recombination experiments in which the mesenchymal tissues of these two types of gland were swapped showed significant alterations in the epithelial gene expression patterns of each gland. The specific alterations in recombined tissues are currently being characterized in depth with attempts to identify soluble factors that might facilitate tissue engineering. A collaboration with the laboratory of Prof. Simon Tran at McGill University is exploring further an approach they developed to protect existing salivary glands from therapeutic radiation-induced damage. Whole-cell homogenates of human bone marrow were found to protect against salivary hypofunction in mice, reproducing with human extracts previous findings with mouse bone marrow. The most notable current finding is that the mononuclear fraction contains this activity, whereas the granulocyte and red blood cell fractions did not. These studies are beginning to elucidate the complex mechanisms that underlie the cell and tissue dynamics involved in craniofacial organ development and maintenance, particularly of salivary glands. Understanding these underlying morphogenetic mechanisms during embryonic development should promote more effective protection and tissue engineering for restoration of damaged organ function.