The in vivo functions of insulin-like growth factor signaling during zebrafish development.

It is becoming increasingly clear that investigations into the pleiotropic functions of insulin-like growth factor (IGF) signaling have revealed a complex system of growth regulation. IGF signaling affects vertebrate; physiology through classic endocrine regulation, and also through paracrine and autocrine mechanisms, altering cell growth, proliferation, differentiation, migration, and survival. The essentiality of IGF signaling for vertebrate development was first demonstrated using knockout mouse models; however, subsequent attempts to investigate the cellular functions of IGF signaling were significantly hindered due to the fact that the mouse embryo develops in utero. To address the outstanding questions concerning the cellular functions of IGF signaling during vertebrate embryogenesis, I took advantage of the rapid, ex utero development, experimental versatility, and genetic tractability of an alternative vertebrate model, the zebrafish (Danio rerio). Recent studies have shown that zebrafish possess all the components of an evolutionarily conserved IGF signaling pathway, including two distinct IGF type 1 receptors (IGF1Rs), termed IGF1Ra and IGFI1Rb , that mediate the biological actions of IGFs. The ubiquitous expression of IGFs and both IGF1Rs throughout zebrafish embryogenesis is consistent with a requirement for IGF signaling for the normal development of nearly every embryonic tissue. Indeed, using a loss-of function approach, I showed that IGF1R deficiency caused overall growth retardation, premature developmental arrest, and subsequent embryonic lethality, but no defects in tissue patterning. At the cellular level, IGF1R deficiency increased neuronal apoptosis and caused specific defects in retinal and motoneuron development. Subsequent cell cycle analysis indicated an increased percentage of cells in the G1 phase and a decreased percentage in the S phase in IGF1R-deficient embryos, independent of apoptotic inhibition. Although analysis of the functional overlap and/or functional distinction between IGF1Ra and IGF1Rb indicated significant redundancy in the regulation of embryonic growth and developmental timing, IGF1Rb was found to be specifically required for promoting spontaneous muscle contractility, motoneuron formation, and primordial germ cell (PGC) migration and survival. Together, these results provide novel insight into the cellular basis for IGF actions during vertebrate embryogenesis and into the functional evolution of the IGF1R/insulin receptor gene family.Ph.D.Biological SciencesCellular biologyMolecular biologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/126284/2/3238079.pd