Research Groups

Our projects can be divided into two main groups:

1. SIGNALING: how morphogen and hormonal signaling coordinates growth, metabolism, and developmental progression.

2. MECHANICS: how physical interactions of cells with each other and their boundaries regulates tissue growth and morphogenesis.

I. MORPHOGEN & HORMONAL SIGNALING

The Hedgehog protein is an example of a morphogen – a secreted signaling molecule that can travel through a tissue and influence gene expression in target cells in a concentration-dependent manner. Hedgehog proteins are highly conserved and regulate tissue growth and patterning - both during embryonic development and during adult tissue homeostasis. Mutations that constitutively activate Hedgehog signaling are extremely common in cancer. We are interested in the interplay between Hedgehog signaling and metabolism that is involved in regulating growth. The Hedgehog pathway is unusual in the degree to which its pathway components are influenced by lipids and their metabolites. Conversely, Hedgehog signaling is emerging as an important regulator of cellular and organismal metabolism. How does the state of cell/organismal metabolism influence Hedgehog signaling at the cell biological level? How does Hedgehog signaling influence cell metabolism during normal growth and development? How does this reciprocal relationship affect developmental growth and adult homeostasis?

Studying metabolism and tissue growth additionally requires an understanding of systemically circulating hormones. Thus, we also aim to study how morphogens like Hedgehog interact with hormones to connect tissue growth to organismal growth, nutrition, and developmental progression. Insulin is a conserved, systemically circulating hormone that is produced and secreted by the brain and relates information on nutrition to the entire animal. In Drosophila, there are 7 insulin-like peptides and one receptor, and activation of the pathway is known to alter metabolism in many model systems. Another major circulating hormone is the steroid ecdysone, which is made in the ring gland near the brain and systemically coordinates growth and developmental progression. How do these hormones affect metabolism and patterning in distant tissues? How is their production coordinated and responsive to different environmental conditions?

Multiple forms of secreted Hedgehog:

Hedgehog ligands can be released in several different forms, depending on whether they are lipid modified. Hedgehog can be covalently modified by two important metabolites: cholesterol and palmitic acid. This doubly lipid modified form requires special cell biological mechanisms for its release. We found that lipoprotein particles can act as vehicles for Hedgehog release – both in Drosophila and in mammals. Hedgehog proteins can also be released in a non-lipid-modified form. In both mammalian cells and in Drosophila, this form synergizes with the lipoprotein-associated form to activate signaling.

One function that is clearly unique to the lipoprotein-associated form of Hedgehog is the ability to block the repressive activity of lipoprotein lipids on the Hedgehog signal transduction pathway. Our findings suggest that lipids contained in lipoproteins are mobilized by the Hedgehog receptor, Patched, to repress the activity of the 7-pass transmembrane protein Smoothened when Hedgehog is absent. Our data suggest that endocannabinoids carried on lipoproteins are endogenous inhibitors of Smoothened activity.

We are using mammalian cell culture to investigate how different forms of Hedgehog affect pathway activation and how they interact with one another to affect signaling output. In addition, we are studying Hedgehog signaling in an endogenous producing tissue, the mouse adrenal gland, to understand more about how it is secreted and what regulates its signaling range.

The connection between patterning and metabolism:

Hedgehog proteins have been shown to promote aerobic glycolysis in some tumor models, but their role in normal development has remained less clear. We are studying the relationship between glycolysis and Hedgehog proteins using the Drosophila wing disc, a well-established model system for studying developmental growth and patterning. In this system, we have also observed that many of the patterning systems that are required for tissue growth are transcriptionally affected by changes in hormonal signaling. Thus, changes in systemic hormonal signaling can affect both patterning and metabolism. We are investigating precisely how metabolism is changed in response to both hormonal and morphogen signaling. We are also further probing the multiple potential ways that insulin proteins affect tissue and organismal growth.

References

Palm, W., Swierczynska, M, Kumari, V., Erhart-Bornstein, M., Bornstein, S., and Eaton, S.* (2013)  Conserved functions of lipoproteins in secretion and signaling of Hh proteins. P.L.o.S Biol. 11(3): e1001505. doi:10.1371/journal.pbio.1001505

Panáková, D., Sprong, H., Marois, E., Thiele, C., and Eaton, S*. (2005). Lipoprotein particles carry lipid-linked proteins and are required for long-range Hedgehog and Wingless signalling. Nature 435, 58-65. 

Eugster, C., Panakova, D., Mahmoud, A., and Eaton, S*. (2007). Lipoprotein-heparan sulfate interactions in the Hedgehog pathway. Dev Cell 13, 57-71. 

Helena Khaliullina, Julio Sampaio, Andrej Shevchenko and Eaton, S.* Lipoproteins carry endocannabinoids that repress the Hedgehog pathway.  In revision.  See BioArXiv doi: 10.1101/000570

Rodenfels, J., Lavrynenko, O., Ayciriex, S., Sampaio, J., Shevchenko, A. and Eaton, S.* Production of circulating Hedgehog by the intestine couples nutrition to growth and development. (2014) Genes and Dev. in press.

Swierczynska, M., Mateska, I., Peitzsch, M., Bornstein, S., Chavakis, T., Eisenhofer, G, Lamounier-Zepter, V., and Eaton, S.*. Changes in morphology and function of adrenal cortex in mice fed a high fat diet. (2014) International Journal of Obesity doi: 10.1038/ijo.2014.102

Khaliullina H, Panáková D, Eugster C, Riedel F, Carvalho M, Eaton S.* (2009). Patched regulates Smoothened trafficking using lipoprotein-derived lipids. Development. 136, 4111-21.