¹Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02114, USA

²Department of Obstetrics and Gynecology, University of Tokyo, Faculty of Medicine, Tokyo 113-8655, Japan

³Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA

⁴Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan

⁵Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, and Departments of Pathology and Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA

Correspondence to: J L Tilly, Massachusetts General Hospital, VBK137C-GYN, 55 Fruit Street, Boston, Massachusetts 02114, USA. Tel: 1-617-724-2182; Fax: 1-617-726-7548; E-mail: jtilly@partners.org

Edited by G Salvesen

^bY Morita and DV Maravei contributed equally to this study

It is well established that programmed cell death claims up to two-thirds of the oocytes produced during gametogenesis in the developing fetal ovaries. However, the mechanisms underlying prenatal germ cell loss in females remain poorly understood. Herein we report that caspase-11 null female mice are born with a reduced number of oocyte-containing primordial follicles. This phenotype is likely due to failed cytokine processing known to occur in caspase-11 mutants since neonatal female mice lacking both interleukin (IL)-1 and IL-1 also exhibit a reduced endowment of primordial follicles. In addition, germ cell death in wild-type fetal ovaries cultured ex vivo is suppressed by either cytokine, likely via ligand activation of type 1 IL-1 receptors expressed in fetal germ cells. Normal oocyte endowment can be restored in caspase-11 null female mice by simultaneous inactivation of the gene encoding the cell death executioner enzyme, caspase-2. However, caspase-2 deficiency cannot overcome gametogenic failure resulting from meiotic recombination defects in ataxia telangiectasia-mutated (Atm) null female mice. Thus, genetically distinct mechanisms exist for developmental deletion of oocytes via programmed cell death, one of which probably functions as a meiotic quality-control checkpoint that cannot be overridden. Cell Death and Differentiation (2001) 8, 614-620

apoptosis; cell death; oocyte; ovary; caspase; ATM; Bax

ATM; ataxia telangiectasia-mutated gene product (Atm, gene designation); ATR, ataxia telangiectasia-and RAD3-related protein; IL-1, interleukin-1; LIF, leukemia inhibitory factor; SCF, stem cell factor (Steel gene product).