Genetics of Growth Control

All animals develop from a fertilized zygote. The development of a zygote depends on cell proliferation for generating tissues and organs. Abnormal regulation of cell proliferation results in various growth defects, including cancer. Genetic approaches have been pivotal for finding essential growth control genes and signaling mechanisms such as NotchNotch, WntWnt, Hedgehog, and Hippo signaling pathways. This chapter will focus on the Hippo pathway as an example of genetic analysis of growth regulation. Conventional mutagenesis studies identified many tumor suppressortumor suppressor mutations that cause tumorous tissue growth in homozygous mutant animals. A different strategy of using mosaic clones led to the discovery of a new group of tumor suppressors, such as warts (wts) and salvador (sav). We will review how these mutants were isolated and how these genes are related. Subsequent studies found another gene, hippo (hpo), whose loss results in tumorous growth. These three genes form the core components of the Hippo pathway that suppress cell proliferation while promoting cell death. We will examine genetic studies that revealed the functional relationship between these core factors. The next question is how the Hippo pathway regulates tissue growth. A key finding is the YorkieYorkie (Yki) protein that activates transcription to promote growth. The Hippo pathway directly antagonizes Yki to suppress organ growth. We will discuss the mechanism that links Hippo and Yki activities and compare the Hippo pathways in Drosophila and mammals.