Friday, December 6, 2024
12/6/2024
The FoxA family of winged-helix DNA-binding transcription factors (TFs) play major roles in the development of many organs in vertebrate embryos. In some cases, they are proposed to be determinants of specific cell fates because they are expressed early and continuously in forming organs, and they are capable of what has been referred to as “pioneer” function – the ability to bind their target motifs even in closed chromatin, whereupon they can “open” that chromatin to make it accessible to other key tissue-specific “settler” TFs. Combined, the pioneer and settler TFs activate expression of the genes controlling tissue morphogenesis, specialization and homeostasis through their sequence-specific interactions with the corresponding target gene enhancers. As with the vertebrate FoxA TFs, the single FoxA orthologue in Drosophila, known as Fork head (Fkh), plays major roles in the formation of multiple organs and in controlling the survival, morphology and physiology of the salivary glands (SG). The relative simplicity of the Drosophila embryonic SG, the non-redundancy in Fkh function, the short development time, ex utero development, and the huge armamentarium of excellent genetic tools make this an ideal model system for testing current models for vertebrate FoxA protein function, for uncovering the mechanisms by which FoxA proteins coordinate morphogenesis with tissue-specific physiological specialization, and for finding and characterizing the downstream effectors that directly impact overall organ architecture and organ placement. In Aim 1, we propose to learn how Fkh works with two other early-expressed SG TFs – Sage and Senseless (Sens) – to regulate expression of the salivary gland “secretome”. Based on earlier findings, these studies will challenge the notion that Fkh has the same pioneering function that has been proposed for the vertebrate FoxA TFs. In Aim 2, we propose to discover and characterize the partner SG TFs and downstream effectors that mediate the FoxA-driven morphological events that transform the two-dimensional salivary gland primordia into three dimensional internalized epithelial secretory organs. These studies will be among the first to reveal how FoxA proteins partner up to drive the morphological changes that underlie tissue development. In Aim 3, we characterize three Fkh morphogenetic targets that help coordinate the abundance, localization and activities of two major players in tissue remodeling – non- muscle Myosin II and the sub-apical transmembrane protein Crumbs. As new targets are discovered (through the earlier aims), we will also determine where, when and how newly discovered morphogenetic players contribute to overall tissue architecture.
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