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

Abstract

<p>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 <em>Drosophila melanogaster</em> 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 <em>Drosophila p53</em> (<em>p53</em>). Mutations in <em>p53</em> 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 <em>p53</em> is required for germ cell death, but not migration. To our knowledge, this is the first report of a loss-of-function phenotype for <em>Drosophila p53</em> in a non-sensitized background. The <em>p53</em> phenotype is remarkably similar to that of <em>outsiders</em> (<em>out</em>) mutants. Here, we show that the <em>out</em> gene encodes a putative monocarboxylate transporter. Mutations in <em>p53</em> and <em>out</em> show nonallelic noncomplementation. Interestingly, overexpression of <em>p53</em> in primordial germ cells of <em>out</em> mutant embryos partially suppresses the out germ cell death phenotype, suggesting that <em>p53</em> functions in germ cells either downstream of <em>out</em> 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.</p>