Programmed cell death of primordial germ cells in Drosophila is regulated by p53 and the Outsiders monocarboxylate transporter.

ABSTRACT

Primordial germ cell development uses programmed cell death to remove abnormal, misplaced or excess cells. Precise control of this process is essential to maintain the continuity and integrity of the germline, and to prevent germ cells from colonizing locations other than the gonads. Through careful analyses of primordial germ cell distribution in developing Drosophila melanogaster embryos, we show that normal germ cell development involves extensive programmed cell death during stages 10-12 of embryogenesis. This germ cell death is mediated by Drosophila p53 (p53). Mutations in p53 result in excess primordial germ cells that are ectopic to the gonads. Initial movements of the germ cells appear normal, and wild-type numbers of germ cells populate the gonads, indicating that p53 is required for germ cell death, but not migration. To our knowledge, this is the first report of a loss-of-function phenotype for Drosophila p53 in a non-sensitized background. The p53 phenotype is remarkably similar to that of outsiders (out) mutants. Here, we show that the out gene encodes a putative monocarboxylate transporter. Mutations in p53 and out show nonallelic noncomplementation. Interestingly, overexpression of p53 in primordial germ cells of out mutant embryos partially suppresses the out germ cell death phenotype, suggesting that p53 functions in germ cells either downstream of out or in a closely linked pathway. These findings inform models in which signaling between p53 and cellular metabolism are integrated to regulate programmed cell death decisions.