Editors' ChoiceDevelopmental Biology

Notch for nucleotide sensing

Sci. Signal.  09 Feb 2016:
Vol. 9, Issue 414, pp. ec27
DOI: 10.1126/scisignal.aaf4220

Nutrient availability affects germline development and fertility. In the nematode Caenorhabditis elegans, the target of rapamycin complex 1 (TORC1) and insulin signaling couple germline development to the availability of amino acids and glucose, respectively. Chi et al. found that Notch signaling links the availability of nucleotides, which must be abundant to support DNA replication, to germline development. Worms lacking the cytidine deaminases CDD1 and CDD2 cannot salvage pyrimidines from nutrients and rely on de novo biosynthesis for pyrimidines. These animals were fertile only when their bacterial food source was supplemented with pyrimidines or when they were fed a strain of bacteria carrying a mutation that caused uridine to accumulate in the bacteria. Compared with the gonads of wild-type animals reared on a low-uridine diet (WT:low-U), the gonads of cdd1–/–;cdd2–/– double mutants fed the same diet (cdd1–/–;cdd2–/–;low-U) were smaller and characterized by mitotically arrested germline cells, fewer meiotic cells, and the absence of gametes. The Notch homolog abnormal germline proliferation 1 (GLP-1) is abundant in the distal region of the gonad and maintains germ cell proliferation by blocking the mitosis-to-meiosis transition. Expression of a constitutively active form of GLP-1 partially restored germline mitosis in cdd1–/–;cdd2–/–;low-U animals, but genetic manipulations that increased insulin or TORC1 signaling did not. GLP-1 was less abundant in the germlines of cdd1–/–;cdd2–/–;low-U animals than in the germlines of WT;low-U animals. Uridine supplementation restored normal GLP-1 abundance in the mutants. Experiments with a fluorescent glp-1 reporter suggested that sequences in the 3'-untranslated region of the glp-1 transcript mediated the effects of uridine availability on GLP-1 abundance. GLP-1 blocks the mitosis-to-meiosis transition by inhibiting mitogen-activated protein kinase (MAPK) signaling. The germlines of cdd1-/-;cdd2-/-;low-U animals exhibited increased MAPK signaling compared with controls, and knocking down the MAPK MPK-1 increased the number of mitotic cells. Although the mechanism by which nucleotide availability is sensed and communicated to GLP-1 remains unknown, these findings identify a Notch-mediated pathway coupling this type of nutrient to regulation of germline development that is complementary to the nutrient-responsive TORC1 and insulin pathways (see Shi and Murphy).

C. Chi, D. Ronai, M. T. Than, C. J. Walker, A. K. Sewell, M. Han, Nucleotide levels regulate germline proliferation through modulating GLP-1/Notch signaling in C. elegans. Genes Dev. 30, 307–320 (2016). [PubMed]

C. Shi, C. T. Murphy, Feeding the germline. Genes Dev. 30, 249–250 (2016). [PubMed]