Holly Ingraham, PhD

Our current biological interest lies in the development of a neuroendocrine center, the ventromedial hypothalamus (VMH), which functions as a central relay station to control both metabolic homeostasis and reproductive behavior. Because the hypothalamus remains poorly defined at a molecular level, we used gene profiling to identify novel genes that mark subsets of neurons within this brain region ( Kurrasch et al.2007). Presumably these markers participate in VMH development and function – the importance of these candidate genes is now being tested using standard molecular biology and mouse genetics. In addition with H. Baier's lab at UCSF we used a forward genetic screen in zebrafish and found 5 mutants disrupted in early hypothalamic patterning (Kurrasch et al., 2009). We are now asking how environmental factors influence the development and formation of the VMH. Indeed we recently showed that the widely used herbicide atrazine activates endocrine gene networks. This study was published in PloS One (Suzawa and Ingraham, 2008). Our paper was discussed on Talk of the Nation NPR’s Science Friday - May 9th, 2008 and selected by the Faculty 1000 of Biology as a Must Read paper.

We also study how a group of nuclear hormone receptors are activated, in particular members of the NR5A subfamily. NR5A receptors are critical for development and function of the endocrine system. In the last several years our lab used a structural approach to show that phospholipids can serve as ligands for NR5A1 nuclear receptors, such as SF-1 or LRH-1. We are now determining how these phospholipids ligands affect receptor activity. As with many transcriptional regulators, NR5A receptors are also richly modified by posttranslational events including phosphorylation and sumoylation. We believe that NR5A receptors represent an ideal model system for investigating how sumoylation alters gene expression. Using both biochemical and mouse genetics we are finding that sumoylation represents an important modification for directing cell specification during development. Our recent work by Campbell et al. 2008 suggests that some target genes will be sumo-sensitive while others will be much less sensitive. This hypothesis is being tested in an in vivo mouse model system