Holly Ingraham, Ph.D.
For several years my laboratory has studied the basic mechanisms underlying endocrine tissue development. We are focused on understanding how a subset of nuclear receptors contributes to embryonic and adult endocrine biology. We use a broad range of techniques including molecular biology, mouse genetics and structural biology to answer questions we pose. In mice, targeted disruption of the orphan nuclear receptor, steroidogenic factor 1 (sf-1) leads to the loss of multiple endocrine tissues. Our work also shows that sf-1 gene dosage is crucial for organ development and organ “scaling”, that is to say, for maintaining and achieving proper organ size. As such, sf-1 heterozygous mice exhibit deficits in adrenal development resulting in an impaired response to stress. We are currently investigating why SF-1 gene dosage affects organ size. A new and growing focus for the lab is on hypothalamic development. Despite the fact that this region of the brain regulates diverse behaviors, it is still poorly defined at the molecular level. However, recent genetic discoveries of the leptin and orexin pathways, and their respective roles in satiety or sleep, have underscored the importance of the hypothalamus as a master controller of innate or non-cognitive behaviors. Our recent work shows that SF-1 controls terminal differentiation of the ventromedial hypothalamic (VMH) neurons. We are now developing genetic tools using mouse models to study the development and function of the VMH. Ultimately, we hope to understand the underlying molecular mechanisms of behaviors controlled by the VMH, including sexual and feeding behaviors.
Our other major focus is directed at understanding how orphan nuclear receptors are activated – do they need a ligand, and if not, how are they regulated? To this end we have studied the role of posttranslational modifications on receptor activity, including both phosphorylation and SUMOylation. Our collective data support the idea that nuclear receptor phosphorylation promotes interdomain crosstalk and hence, plays a major role in modulating orphan receptor activity as well as in ligand-dependent receptor activity. We have recently obtained the high-resolution crystal structure of LRH-1 in collaboration with Dr. R. Fletterick. LRH-1 is the closest homologue of SF-1 and key regulator of estrogen production in the ovary, breast and brain. These studies addressing non-ligand receptor activation are particularly relevant in understanding how late stages of breast and prostrate cancer become hormone resistant.