Characterization of multiple functions of EGL-38, a PAX2/5/8-related protein in Caenorhabditis elegans

During animal development, some key transcription factors, such as paired-box proteins (PAX proteins), regulate target gene expression in multiple tissues, and thereby control multiple biological processes. Given the high conservation of PAX proteins among animal species, studies using the simple organism Caenorhabditis elegans (C. elegans) can provide insight into the role of Pax genes in development of all animals.; In C. elegans, a Pax2/5/8 related gene egl-38 functions in multiple tissues. For example, egl-38 activity is necessary for proper development of the hermaphrodite reproductive system and mating structure in the male tail. egl-38 is also critical during embryogenesis. In the germline, EGL-38 and another Pax protein PAX-2 can influence germline cell death. Although multiple functions of EGL-38 have been identified, there is less known about the specific molecular details of how EGL-38 regulates target genes and how it is controlled by upstream regulators. To understand how a Pax protein mediates different outcomes in different cell types, it is necessary to elucidate the underlying logic behind EGL-38 tissue and target gene specificity. In addition, identification of new egl-38 target genes may uncover novel roles for Pax2/5/8 genes in C. elegans development.; In Chapter 2 of this thesis, I show that EGL-38 coordinates with a protein complex formed between CES-2 and ATF-2 to modify the temporal transcription of a gene, lin-48. This combination influences the function of lin-48 in determining excretory system development and anatomy, but not in its post-embryonic role in influencing excretory system physiology and salt tolerance. In appendix 2 and other work, we showed that EGL-38 and PAX-2 directly regulate ced-9, a bcl-2 like anti-apoptotic gene, to influence germline cell death. In Chapter 3, the impact of the tyrosine receptor kinase (RTK) VAB-1 and its ephrin ligands on germline cell death is characterized. It is possible that VAB-1, acting through MAPK, regulates EGL-38 and PAX-2. In Chapter 4, a novel function for EGL-38 in mediating the C. elegans immune response to a gram-positive bacterium Microbacterium nematophilum, was identified by employing microarray analysis.; Exploring the upstream regulators and downstream targets of Pax genes and how PAX proteins regulate their targets will allow us to further understand the mechanisms of animal developmental processes. Because PAX proteins are present and conserved among all animals, these results may shed light on human developmental disorders and diseases.