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 Paxgenes in development of all animals.
In C. elegans, a Pax2/5/8related gene egl-38functions in multiple tissues. For example, egl-38activity is necessary for proper development of the hermaphrodite reproductive system and mating structure in the male tail. egl-38is 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-38target genes may uncover novel roles for Pax2/5/8genes in C. elegansdevelopment.
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-48in 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-2like 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. elegansimmune response to a gram-positive bacterium Microbacterium nematophilum, was identified by employing microarray analysis.
Exploring the upstream regulators and downstream targets of Paxgenes 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.