Research Groups

Morphogen signaling

Hedgehog proteins are highly conserved secreted signaling molecules that 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, and its role 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?  Does this reciprocal relationship allow feedback interactions that could control growth? 


Hedgehog is secreted in multiple forms

Hedgehog ligands can be released in several different forms that depend on whether or not the proteins are lipid modified.  Hedgehog can be covalently modified by two important metabolites: cholesterol and palmitic acid.  This doubly lipid modified form has a high affinity for cell membranes, and 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 active signaling. We are trying to find out what mechanisms control the production and release of non-lipid-modified Hedgehog, how cells decide on the balance between these two forms.  Do cellular levels of cholesterol or palmitoylCoA play any role in this? We would also like to understand how they affect the Hedgehog signal transduction pathway differently.

Lipoprotein lipids repress Hedgehog signaling – lipoprotein-associated Hedgehog blocks their repressive activity

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. Patched resembles proteins of the RND transporter family, which are involved in lipid trafficking. Smoothened activity can be repressed by a variety of synthetic small molecules, and our data suggest that endocannabinoids carried by lipoproteins could be endogenous inhibitors of Smoothened activity.  Lipoprotein-associated Hedgehog can block inhibition by lipoproteins lipids – in this context, Hedgehog appears to act as a sort of bar code to tell cells what to do with the lipids in lipoprotein particles. The non-lipid modified Hedgehog cannot do this. Furthermore, lipoproteins carry heparin sulfate proteoglycans that can modify the activity of lipoprotein-associated Hedgehog – a regulatory mechanism not available to non-lipid-modified Hedgehog. Now we need to understand how the activity of the non-lipid-modified form differs in a way that allows it to synergize with the lipoprotein form.

It will be extremely interesting to find out what mechanisms control the amount of endocannabinoids present in circulating lipoproteins – regulating circulating endocannabinoid levels could allow the metabolic state of the organism to influence local Hedgehog signaling. This could be important during development, when the growth and patterning of developing tissues must be sensitive to organismal nutrient availability.  In principle, it could also allow metabolism in adult animals to influence the activity of Hedgehog in stem cell niches.

Hedgehog circulates systemically on lipoproteins and acts as an endocrine hormone

The lipoprotein-associated form of Hedgehog is particularly important in circulation. Humans, mice and Drosophila all produce systemic forms of Hedgehog (or Sonic Hedgehog) that circulate on lipoprotein particles.  In flies, circulating Hedgehog acts as an endocrine hormone that is produced in the intestine upon starvation.  It signals to the fat body (similar to vertebrate liver and adipose tissue) to promote fat mobilization and slow growth, and to the prothoracic gland to block production of ecdysteroids (the insect steroid hormones).  Thus, release of Hedgehog on systemically circulating lipoproteins couples growth and development to nutritional conditions and helps larvae survive starvation.

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.