The signal transduction pathways that regulate cellular morphogenesis are fundamentally important for cell growth and development. Therefore, the goal of this application is to identify novel regulators of morphogenesis that control the ability of the human fungal pathogen Candida albicans to grow in different morphologies in response to external cues. Growth as small buds is thought to promote dissemination through the bloodstream, whereas a transition to forming elongated hyphal cells promotes invasive dissemination into tissues. However, the signal pathways that regulate this important transition from budding to hyphal growth are not understood. Although transcriptional studies have shown that overexpression of a transcriptional inducer (e.g. UME6) or deletion of a repressor (e.g. NRG1) promotes hyphal growth, it is not clear how the resulting changes in gene expression influence key morphogenesis components, such as Cdc42. Therefore, the goal of this application is to identify the signal pathways that regulate the components that directly mediate morphogenesis to form hyphae. An innovative aspect of these studies is that the approaches are designed to identify how the sugar N-acetylglucosamine (GlcNAc) induces hyphal morphogenesis. GlcNAc is emerging as an important signaling molecule in a wide range of organisms. This potent inducer of hyphal responses is found at sites of C. albicans growth in vivo due to remodeling of bacterial cell wall peptidoglycan, fungal cell wall chitin, and the extracellular matrix of human cells. Previous studies showed that GlcNAc has to be taken up by cells to induce hyphae, but it does not have to be metabolized. This permits GlcNAc to be studied as a signaling molecule independent of potential effects on nutrition. Furthermore, a mutant that lacks the capacity to metabolize GlcNAc can be induced to form hyphae without obviously inducing the hyphal- specific genes. This indicates that GlcNAc is capable of stimulating a separate morphogenesis signal that is distinct from transcriptional responses. Thus, the goals are to identify the novel pathways that induce GlcNAc responses, including activation of a specific cyclin-dependent kinase complex, Hgc1-Cdc28, that promotes hyphal morphogenesis. Studies will also determine the role of novel genes needed for hyphal morphogenesis that were identified by genetic screening. The results are expected to identify new mechanisms that regulate signal transduction and morphogenesis that will serve as an important model for other organisms.
The goal of this application is to identify novel signal transduction pathways that regulate cellular morphogenesis. Specific experiments will define how the human fungal pathogen Candida albicans switches between growing as round budding cells or long hyphal filaments, which underlies its ability to grow invasively into tissues and cause disease. This morphological switch is also significant because it can be regulated by the sugar N-acetylglucosamine, which is emerging as an important signaling molecule in a wide range of organisms from bacteria to humans. The identification of novel GlcNAc signaling mechanisms and regulators of morphogenesis in C. albicans will therefore serve as important models for understanding how these processes are regulated in other organisms.
