2013 Theses Doctoral

Genetic analysis of novel regulators of neuronal migration in Caenorhabditis elegans: the insulin/IGF-1 signaling pathway, a chromatin-binding factor ZFP-1 (AF10) and endogenous RNAi

Kennedy, Lisa Michelle

The generation of functional neural circuitries requires neuronal migration, a central component of proper nervous system development. When defective, it can lead to devastating conditions including epilepsy and mental retardation. In the nematode C. elegans, neurons undergo both short- and long-range migrations that are regulated by conserved pathways. In my thesis study, I explore novel roles for both the insulin/IGF-1 signaling pathway and RNAi factors in neuronal migration by using the embryonic anterior migrations of the hermaphrodite-specific neurons (HSNs) of C. elegans as a model. I demonstrate that the insulin/IGF-1 signaling pathway modulates the activity of the conserved DAF-16/FOXO transcription factor non-autonomously in the hypodermis to regulate HSN migration. Furthermore, I identify PAK-1, a p21-activated kinase, as a downstream target of DAF-16 in the hypodermis. This study is the first to demonstrate a non-autonomous role for both FOXO and Pak1 in neuronal migration. I also implicate a conserved PHD zinc finger protein ZFP-1/AF10 and endogenous RNAi in the regulation of HSN migration. I determine that ZFP-1 affects HSN migration in part through its negative effect on the transcription of the conserved insulin/IGF-1 signaling kinase gene pdk-1 and the modulation of downstream DAF-16 activity. This study expands the limited understanding of the normal developmental roles of both ZFP-1/AF10 and RNAi. Combined, this thesis highlights a requirement for the coordinated activities of DAF-16/FOXO, ZFP-1/AF10 and endogenous RNAi in the establishment of proper neuronal positioning during development.