Ingraham Lab Research Areas
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. This brain region is still poorly defined at a molecular level. Our recent study has begun to define the molecular markers of this region (see Kurrasch et al. PDF). By using microarray technology, we have identified new markers that will presumably 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 with a disruption in early hypothalamic patterning. Two have been identified as NSF and Rx3; the other three are currently being mapped. In the course of these studies we have discovered remarkable conservation in the organization of the mammalian and teleost neuroendocrine system. We have begun to ask how environmental factors influence the development and formation of the VMH.
We are studying how 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 has demonstrated that phospholipids can serve as ligands for nuclear receptors such as SF-1 or LRH-1. We are determining how these phospholipids affect receptor activity using biochemistry and structural biology.
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. To this end we have used both a biochemical and a mouse genetic approach to ask how sumoylation represses gene expression and how this modification affects genetic programs in vivo. Our recent work by Campbell et al. (In revision) suggests that some sites within target genes will be sumo-sensitive while others will be much less sensitive. This hypothesis is being tested using an in vivo knock-in of the SF-1 sumo mutant.
Another area that we are actively pursuing is how the widely used herbicide atrazine activates NR5A receptors. Our latest study in this area was published in PloS One (see Suzawa and Ingraham PDF) and was covered on Talk of the Nation NPR’s Science Friday - May 9th, 2008. This work was also selected by Faculty 1000 of Biology as a Must Read paper on May 28th, 2008.
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