Gap junctions deliver malonyl-CoA from soma to germline to support embryogenesis inCaenorhabditis elegans

Abstract

Gap junctions are virtually ubiquitous in metazoans and play critical roles in many important biological processes, including electrical conduction and development. Despite this ubiquity, only a small number of molecules passing through gap junction channels have been definitively linked to specific functions.We isolated gap junction channel mutants that reduce junctional coupling between the soma and germ cells in the C. elegans gonad. We use genetic methods to show that malonyl-CoA, the rate-limiting substrate for fatty acid synthesis (FAS), is produced in the soma and delivered through gap junctions to the germline; there it is used by fatty acid synthase to critically support embryonic development. Tissue separation of malonyl-CoA production from its site of utilization facilitates somatic control of germline development and reproduction.Further, our results suggest that this metabolic outsourcing may be a strategy by which the soma communicates nutritional status to the germline.Gap junctions are clusters of intercellular channels allowing direct passage of small molecules between coupled cells. They are widespread in multicellular organisms, though different gene families encode the protein subunits in invertebrates (innexins) and vertebrates (primarily connexins) 1 . While the capability of small molecules to pass through gap junctions can be shown readily in cultured cells, identification of essential molecules that must pass through channels in vivo is challenging. Additionally, disruption of gap junction coupling can affect cell adhesion 2 , and resultant defects in intercellular communication may not necessarily relate to the passage of molecules through junctional channels.In C. elegans, germ cells are coupled throughout their development to the somatic gonad by gap junctions 3 . Germ cells progress in assembly-line fashion through the early stages of meiosis (Fig. 1a). Gonadal gap junctions have been implicated in germ cell proliferation, oocyte growth, regulation of oocyte meiotic maturation, early embryogenesis and sperm guidance 3-7 . Gap junction hemichannels (half-channels) in the somatic gonad are comprised of the recently duplicated innexins INX-8 and INX-9; apposing germ cell hemichannels are heteromeric and consist of INX-14 in conjunction with either INX-21 or INX-22 ( Supplementary Fig. 1). Germ cells fail to proliferate in inx-8(0) inx-9(0) mutants, at a point upstream of, or parallel to, GLP-1/Notch activation of germ cells by Delta class ligands LAG-2 and APX-1. These ligands are produced in the distal tip cell (DTC) that maintains the proliferative stem cell niche 4,[8][9][10] .Germ cell proliferation can be rescued in inx-8(0) inx-9(0) mutants to half the level of wild type by driving inx-8 expression in the DTC with the lag-2 promoter 3 . In these animals, gap junctions between soma and germline are established in the distal gonad arm, but ostensibly not in the proximal arm; many resultant embryos exhibit characteristics of the Pod phenotype (Polarity and Osmotic sensitivity Defect)...