Regulation of Body Size by TGF-β Signaling

Abstract

Nearly all life history traits scale with body size, imparting incredible importance on control of growth and size during animal development. Nutrition, genetic and environmental inputs influence the growth rate during development to determine final body size. These inputs are processed by the insulin/insulin-like growth factor signaling pathway (IIS), which is the major regulator of growth, and other pathways, like TGF-β, which modulate tissue growth or IIS. Mutations in the gene coding for the Drosophila TGF-β ligand Activinβ (Actβ) cause reduced final body size and accelerated growth termination. Using the Gal4/UAS system, I show Actβ is expressed in distinct cell types in the nervous system. Using rescue experiments, I show the Actβ phenotypes can be rescued by overexpression of Actβ in some, but not all, of the cell types in which it is endogenously expressed. Additionally, the growth rate of Actβ mutants is reduced, demonstrating the size phenotype is not simply due to early growth termination from precocious timing. Muscle-specific knockdown of the TGF-β signaling transducer/transcription factor dSmad2 also reduces body size, identifying muscle is a target tissue of the Actβ signal. The change in body size is due to a reduction in the size of skeletal muscles, not a systemic reduction in size. Autophagy markers are upregulated in Actβ mutants but, surprisingly, overexpression of autophagy regulators does not rescue the Actβ size phenotype, indicating Actβ regulation of autophagy is TOR-independent. These results provide new insights into mechanisms of body size and muscle size control during animal development. This thesis details the functions of Actβ in the regulation of body size and developmental timing. Chapter 2 describes the study of how Actβ controls body size and developmental timing. Chapter 3 investigates the roles of Actβ in regulating metabolism and IIS.