Editors' ChoiceDevelopmental Biology

Endocrine Hedgehog

Sci. Signal.  09 Dec 2014:
Vol. 7, Issue 355, pp. ec340
DOI: 10.1126/scisignal.aaa4309

Hedgehog (Hh) is a secreted ligand that influences cell fate and behavior locally. Lipoprotein-associated forms of Hh are also present in the circulation of fruit fly larvae, suggesting that Hh may also act systemically. In fruit flies, growth and developmental timing are coupled; fly larvae pupariate only after reaching a critical weight. Using tissue-specific RNA interference, Rodenfels et al. identified the enterocytes of the midgut as a source of circulating Hh in Drosophila melanogaster. Larvae lacking Hh grew faster and pupariated earlier than controls; restoring Hh production specifically in midgut enterocytes rescued these phenotypes. Reducing Hh production by midgut enterocytes caused larvae to pupariate earlier than, but at the same body size as, controls. Conversely, overexpressing Hh in midgut enterocytes increased the abundance of circulating Hh and delayed larval growth and pupariation. Midgut-derived Hh was not required for gut development or homeostasis, implying that its effects were mediated by other organs. Interfering with mediators of Hh signaling in the fat body, a tissue functionally analogous to the vertebrate liver and adipose tissue, reduced the ability of circulating Hh to slow growth. Circulating Hh also delayed the production of the steroid hormone ecdysone by the prothoracic gland. This gland produces a short pulse of ecdysone that commits the larva to pupariation once the critical weight has been reached. Circulating Hh was not required for normal triacylglycerol (TAG) metabolism in well-fed animals, but was required for mobilization of TAG from the fat body during starvation. Starvation caused an increase in hh expression in the midgut, and reducing hh expression in the midgut decreased the amount of time larvae could survive starvation. The fat body does not express hh, but the abundance of Hh in the fat body correlated with the amount of Hh produced by the midgut, and Hh pathway components were required in the fat body for TAG mobilization. Together these results show that circulating Hh produced by the midgut acts as an endocrine signal that controls growth and development in response to nutritional status and regulates metabolism during starvation. Hh has also been implicated in fat storage and glucose metabolism in mice, suggesting that this hormonal function of Hh may be conserved.

J. Rodenfels, O. Lavrynenko, S. Ayciriex, J. L. Sampaio, M. Carvalho, A. Shevchenko, S. Eaton, Production of systemically circulating Hedgehog by the intestine couples nutrition to growth and development. Genes Dev. 28, 2636–2651 (2014). [PubMed]