ABCC5 is required for cAMP-mediated hindgut invagination in sea urchin embryos

Representative micrographs showing accumulation of fluorone-based and bodipy-conjugated chemicals

Representative micrographs showing accumulation of fluorone-based and bodipy-conjugated chemicals

TitleABCC5 is required for cAMP-mediated hindgut invagination in sea urchin embryos
Publication TypeJournal Article
Year of Publication2015
AuthorsShipp L.E, Hill R.Z, Moy G.W, Gokirmak T., Hamdoun A.
JournalDevelopment
Volume142
Pagination3537-3548
Date Published2015/10
Type of ArticleArticle
ISBN Number0950-1991
Accession NumberWOS:000366358700010
KeywordsABC transporter; ABCC5; cAMP; cyclic-nucleotides; Developmental signaling; drug efflux; expression; Gastrulation; lytechinus-variegatus; moat-c; MRP5; multidrug-resistance protein; pigment-cells; Sea urchin; Soluble adenylyl cyclase (sAC); transporter
Abstract

ATP-binding cassette (ABC) transporters are evolutionarily conserved proteins that pump diverse substrates across membranes. Many are known to efflux signaling molecules and are extensively expressed during development. However, the role of transporters in moving extracellular signals that regulate embryogenesis is largely unexplored. Here, we show that a mesodermal ABCC (MRP) transporter is necessary for endodermal gut morphogenesis in sea urchin embryos. This transporter, Sp-ABCC5a (C5a), is expressed in pigment cells and their precursors, which are a subset of the non-skeletogenic mesoderm (NSM) cells. C5a expression depends on Delta/Notch signaling from skeletogenic mesoderm and is downstream of Gcm in the aboral NSM gene regulatory network. Long-term imaging of development reveals that C5a knockdown embryos gastrulate, but similar to 90% develop a prolapse of the hindgut by the late prism stage (similar to 8 h after C5a protein expression normally peaks). Since C5a orthologs efflux cyclic nucleotides, and cAMP-dependent protein kinase (Sp-CAPK/PKA) is expressed in pigment cells, we examined whether C5a could be involved in gastrulation through cAMP transport. Consistent with this hypothesis, membrane-permeable pCPT-cAMP rescues the prolapse phenotype in C5a knockdown embryos, and causes archenteron hyper-invagination in control embryos. In addition, the cAMP-producing enzyme soluble adenylyl cyclase (sAC) is expressed in pigment cells, and its inhibition impairs gastrulation. Together, our data support a model in which C5a transports sAC-derived cAMP from pigment cells to control late invagination of the hindgut. Little is known about the ancestral functions of ABCC5/MRP5 transporters, and this study reveals a novel role for these proteins in mesoderm-endoderm signaling during embryogenesis.

DOI10.1242/dev.126144
Short TitleDevelopment
Impact: 

This study is the first detailed characterization of an ABCC5 transporter in the development of an animal embryo. A key question raised by our work is whether the function of ABCC5 might be evolutionarily conserved. In Caenorhabditis elegans and Danio rerio, ABCC5 may transport heme, and its knockdown causes embryonic lethality and reduced blood cell formation, respectively (Korolnek et al., 2014). In Dictyostelium development, ABCC5 is a candidate cAMP transporter (Miranda et al., 2015). In mammals, studies of ABCC5 in development are sparse, but human ABCC5 is expressed in membranes of amniotic epithelia (Aye et al., 2007), and in cytotrophoblasts and syncytiotrophoblasts (Manceau et al., 2012; Meyer Zu Schwabedissen et al., 2005). The highly regulated expression of this transporter, and clear effects of its perturbation in embryos, underscore its potential to play a central role in developmental signaling.

Student Publication: 
No
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