Editors' ChoiceDevelopment

Extracellular cAMP drives gut morphogenesis

Sci. Signal.  27 Oct 2015:
Vol. 8, Issue 400, pp. ec310
DOI: 10.1126/scisignal.aad7027

Although most often considered an intracellular second messenger, cyclic adenosine monophosphate (cAMP) can also be released from cells to mediate intercellular signaling by binding to and activating cell surface receptors. Shipp et al. found that pigment cells of the Strongylocentrotus purpuratus (sea urchin) embryo exported cAMP through the adenosine triphosphate (ATP) binding cassette (ABC) transporter ABCC5a. Pigment cells are mesodermal derivatives that invaginate along with the gut endoderm during gastrulation. ABCC5a transcripts and ABCC5a protein were most abundant in pigment cells during gastrulation, and knocking down ABCC5a reduced invagination of the gut, resulting in gut prolapse. When overexpressed in embryos, ABCC5a effluxed the dye fluorescein diacetate (FDA), a dye specifically transported by transporters selective for cyclic nucleotides. In wild-type embryos that were transiently exposed to FDA, less FDA accumulated in pigment cells than in other cell types. In contrast, FDA accumulated in the pigment cells of ABCC5a-knockdown embryos. As development progressed, FDA became enriched in the invaginating gut endoderm. Whereas application of membrane-permeable analogs of cAMP or cGMP induced excessive invagination of the gut in wild-type embryos, either compound dose-dependently rescued gut prolapse in ABCC5a-knockdown embryos. Experiments with pharmacological inhibitors demonstrated that the soluble (cytosolic) form of adenylyl cyclase (sAC), the enzyme that converts ATP to cAMP, was also required for gut invagination. sAC transcripts and sAC protein were limited to pigment cells and most abundant during gastrulation. These results indicated that cAMP generated in and released from the pigment cells is important for proper invagination of the sea urchin gut. Whether cAMP acts intracellularly in the endoderm following uptake, as suggested by the accumulation of FDA in the invaginating endoderm, or extracellularly by activating surface receptors remains to be determined.

L. E. Shipp, R. Z. Hill, G. W. Moy, T. Gökirmak, A. Hamdoun, ABCC5 is required for cAMP-mediated hindgut invagination in sea urchin embryos. Development 142, 3537–3548 (2015). [PubMed]