xiii, 48 p. : (col. ill.) A print copy of this title is available through the UO Libraries under the call number: SCIENCE QL537.D76 N57 2007 / Asymmetric cell division (ACD) is a unique mechanism employed during development to achieve cellular diversity from a small number of progenitor cells. Cells undergoing ACD distribute factors for self-renewal at the apical cortex and factors for differentiation at the basal cortex. It is critical for proper development that the mitotic spindle be tightly coupled to this axis of polarization such that both sets of proteins are exclusively segregated into the daughter cells. We use ACD in Drosophila neuroblasts as a model system for understanding the molecular mechanisms that govern spindle-cortical coupling. Neuroblasts polarize Partner of Inscuteable (Pins), Gαi and Mushroom Body Defect (Mud) at the apical cell cortex during mitosis. Gαi and Pins are required for establishing cortical polarity while Mud is essential for spindle-cortical alignment. Gαi and Mud interact through Pins GoLoco domains and tetratricopeptide repeats (TPR) respectively, however it is unclear how Mud activity is integrated with Pins and Gαi to link neuroblast cortical polarity to the mitotic spindle. This dissertation describes how Pins interactions with Gαi and Mud regulate Iwo fundamental aspects of neuroblast ACD: cortical polarity and alignment of the spindle with the resulting polarity axis. I demonstrate that Pins is a dynamic scaffolding protein that undergoes a GoLoco-TPR intramolecular interaction, resulting in a conformation of Pins with low Mud and reduced Gαi binding affinity. However, Pins TPR domains fail to completely repress Gαi binding, as a single GoLoco is unaffected by the intramolecular isomerization. Gαi present at the apical cortex specifies Pins localization through binding this "unregulated" GoLoco. Liberation of Pins intramolecularly coupled state occurs through cooperative binding of Gαi and Mud to the other GoLoco and TPR domains, creating a high-affinity Gαi-Pins-Mud complex. This autoregulatory mechanism spatially confines the Pins-Mud interaction to the apical cortex and facilitates proper apical-spindle orientation. In conclusion, these results suggest Gαi induces multiple Pins states to both properly localize Pins and ensure tight coupling between apical polarity and mitotic spindle alignment. / Adviser: Ken Prehoda