Editors' ChoiceDevelopmental Biology

Family planning for worms

Sci. Signal.  19 Jul 2016:
Vol. 9, Issue 437, pp. ec164
DOI: 10.1126/scisignal.aah5679

Reproduction is energetically expensive. In the hermaphroditic nematode Caenorhabditis elegans, the germline only proliferates if the animal has reached maturity and there are sufficient resources to load the oocytes with the nutrients necessary to support embryonic development. Two studies describe mechanisms that stimulate germline development and enhance germline stem cell (GSC) proliferation in response to nutrients. Nematodes feed on bacteria, which provide essential nutrients, like folates, that animals cannot synthesize de novo. Using primary cultures of GSCs, Chaudhari et al. found that extracts from wild-type bacteria or folates purified from bacteria, but not extracts from bacteria that could not make folates, stimulated GSC proliferation. In vivo, both bacterial extracts and purified folates stimulated germline proliferation. Whereas a particular class of purified folates (10-formyl-tetrahydrofolate-Glun) stimulated GSC proliferation, several other folates that stimulate one-carbon metabolism, including folic acid, failed to induce GSC proliferation. Stimulation of one-carbon metabolism was not required for folates to promote GSC proliferation, but the folate receptor FOLR-1 was required both in vivo and in the cultured GSCs. FOLR-1 was not required for basal GSC proliferation in vivo but was required for folates purified from bacteria to stimulate GSC proliferation. These findings indicate that specific dietary folates stimulate reproductive capacity in C. elegans through a mechanism that is independent of their function as vitamins (see commentary by Walker).

During vitellogenesis (yolk deposition) in C. elegans, fats stored in the intestine are mobilized, transported to the germline by the lipid-binding proteins vitellogenins, and transferred into the developing oocytes. Vitellogenins are encoded by the vit genes and produced in the intestine. Dowen et al. demonstrated that a developmental timing mechanism that operates in the worm hypodermis, which are syncytial cells that cover the external surface of the animal, stimulated the mobilization of intestinal fat stores during the larva-to-adult transition. LIN-4 and LET-7 are microRNAs that are part of the network that controls developmental timing, including the expression of lin-29, which encodes a zinc finger transcription factor produced during the final larval stage. Lin-4, let-7, and lin-29 were required in the hypodermis, not the intestine, for the intestinal expression of the vit genes. Vitellogenin production also required components of mechanistic target of rapamycin complex 2 (mTORC2) and the downstream kinase SGK-1 in the intestine. Additional genetic analyses indicated that activation of SGK-1 promoted cytoplasmic retention PQM-1, a transcription factor that antagonizes fat mobilization when it accumulates in the nucleus. Insulin signaling also activates SGK-1 and represses nuclear accumulation of the transcription factor DAF-16 (homologous to mammalian FoxO,) but DAF-16 was not required for vit expression induced by LIN-29, mTORC2, and SGK-1. These findings link the network that controls developmental timing to the metabolic changes necessary for germline development and provide a potential mechanism by which developmental timing and nutrient-sensing pathways could cooperate to ensure that vitellogenesis is only initiated when conditions are right (see Weaver et al.).

S. N. Chaudhari, M. Mukherjee, A. S. Vagasi, G. Bi, M. M. Rahman, C. Q. Nguyen, L. Paul, J. Selhub, E. T. Kipreos, Bacterial Folates Provide an Exogenous Signal for C. elegans Germline Stem Cell Proliferation. Dev. Cell 38, 33–46 (2016). [PubMed]

A. K. Walker, Germ cells need folate to proliferate. Dev. Cell 38, 8–9 (2016). [PubMed]

R. H. Dowen, P. C. Breen, T. Tullius, A. L. Conery, G. Ruvkun, A microRNA Program in the C. elegans Hypodermis Couples to Intestinal mTORC2/PQM-1 Signaling to Modulate Fat Transport, Genes Dev. 30, 1515–1528 (2016). [PubMed]

B. P. Weaver, A. K. Sewell, M. Han, Time to move the fat. Genes Dev. 30, 1481­–1482 (2016). [PubMed]