Seminar

Systemic Hh coordinates the response to starvation

Jonathan Rodenfels, PhD

The ability of an organism to respond to nutritional stress is critical for its survival. Multiple conserved mechanisms have evolved to sense differences in nutrition and coordinate the organism’s response. Here, we demonstrate that midgut derived and Lipoprotein-associated Hedgehog (Hh) is systemically circulating in the hemolymph of Drosophila. Midgut Hh expression is regulated by nutrition and RNAi mediated knock-down of circulating Hedgehog leads to starvation sensitivity. Loss and gain of function experiments indicate that circulating Hh inhibits growth and developmental progression. In insects, the developmental transitions are regulated by the steroid hormone ecdysone, which is produced by prothoracic gland (PG) of the ring gland (RG). Furthermore, nutritional regulation of growth is in part mediated by the Drosophila fat body (FB).Strikingly, canonical Hedgehog pathway components are present in both tissues, the fat body and PG. In order to understand the Hedgehog mediated function during nutritional stress we ectopically activated or inhibited the Hedgehog signaling pathway specifically in the fat body or in the ring gland. Activation of the pathway in the FB phenocopies the growth inhibition observed with gain of function in circulating Hh. Moreover, pathway activation in the FB leads to a reduction in whole larval fat, glycogen and circulating sugar levels. Pathway activation in the PG results in non-pupariating larvae with strongly reduced transcription of the ecdysone biosynthetic enzyme phantom and a known ecdysone target gene, E74B. In conclusion, we propose a model whereby systemically circulating Hh regulates the organism’s response to nutritional stress by inhibiting growth and developmental progression.