The long-term objectives of this project are to define the cellular regulatory mechanisms that govern cell differentiation in eukaryotes using Dictyostelium discoideum as a model. This system can be used to provide a complete picture of the regulation of a significant biological problem: the integration of individual cells into a multicellular tissue with the proper form and function. Two ABC transporters, RhT and TagA, operate very early in development and the timing of their appearance and the regulation that they effect overlaps with the control of the initiation of development. Several components of the regulatory network that governs the growth to development transition itself were characterized: a novel putative receptor/kinase GdtB, a conserved differentiation-specific protein kinase YakA and a conserved translational regulator PufA. These five regulators are critical links in the regulatory network that controls growth, the decision to initiate development and initial establishment of specific cell types-regulation that is common to all eukaryotes that undergo development. The five proteins include those that are well known and relatively well studied in other species (Rht and PufA), one that is relatively well known but much less well understood (YakA) and two proteins of novel modular design that may presage similar regulators in others systems (TagA and GdtB). GdtB, YakA and TagA each are part of new signaling pathways and studying them may illuminate regulatory systems that are fundamental to all eukaryotes. The function of these signaling pathways in Dictyostelium will be studied by genetic, physiological and genomic methods. As new protein components of these pathways are uncovered, their functions will be determined, and the relationships between them explored, by examining mutant phenotypes, transcriptional profiles and other physiological measures. Transcription levels of most genes in the genome will be measured for all mutants studied and for wild type cells under various conditions. The pattern of gene expression will be interpreted in two ways. First, function will be assigned to genes based on their transcriptional regulation, according to the notion that a gene is expressed when and where it is needed. Second, the pattern of expression of all the genes will be determined for all the mutant strains and we will attempt to assign function to the mutated genes based on this transcriptional phenotype. Describing complex biological pathways is the result of integrating information on many individual components and on their interactions. This is most easily done in relatively simple systems that afford the use of powerful molecular tools, such as Dictyostelium. These descriptions will likely impact our understanding of, and ability to treat, human disease.
| Cabral, Matthew; Anjard, Christophe; Malhotra, Vivek et al. (2010) Unconventional secretion of AcbA in Dictyostelium discoideum through a vesicular intermediate. Eukaryot Cell 9:1009-17 |
| Zhang, Chenyu; Kuspa, Adam (2009) Transcriptional down-regulation and rRNA cleavage in Dictyostelium discoideum mitochondria during Legionella pneumophila infection. PLoS One 4:e5706 |
| Good, J Randall; Cabral, Matthew; Sharma, Sujata et al. (2003) TagA, a putative serine protease/ABC transporter of Dictyostelium that is required for cell fate determination at the onset of development. Development 130:2953-65 |
