Holly A. Ingraham
Research unraveled molecular events controlling endocrine tissue development. Demonstrated that the orphan nuclear receptor, Steroidogenic Factor 1 (SF-1), is a master regulator of the hormone MIS, thereby controlling male sexual differentiation. Envisioned gene dosage of SF-1 would have major consequences for endocrine tissue development, a hypothesis now validated by the large cohort of human SF-1 heterozygous mutants exhibiting endocrine disease. Used SF-1 to examine how orphan nuclear receptors are regulated by atypical phospholipid ligands or by post-translational modifications (PTM). Showed that sumoylation of SF-1 is critical for normal endocrine organogenesis, providing first in vivo example of how this PTM fine-tunes gene expression. With collaborators, solved the crystal structures for ligand binding domains of SF-1 and the closely related receptor, Liver Receptor Homologue-1 (LRH-1), leading to unexpected identification of phospholipids as physiologic ligands for these two nuclear receptors. Showed that nuclear lipid kinases and phosphatases directly remodel SF-1-bound phospholipids, illuminating a novel lipid-based signaling pathway for controlling gene expression.