Essential Role of the Apolipoprotein E Receptor-2 in Sperm Development

Abstract

The apolipoprotein (apo) E receptor-2 (apoER2) is a member of the low density lipoprotein receptor gene family and an important regulator of neuronal migration. It acts as a receptor for the signaling factor Reelin and provides positional cues to neurons that migrate to their proper position in the developing brain. Besides brain formation defects, apoER2-deficient mice also exhibit male infertility. The role of the receptor in male reproduction, however, remained unclear. Here we demonstrate that apoER2 is highly expressed in the initial segment of the epididymis, where it affects the functional expression of clusterin and phospholipid hydroperoxide glutathione peroxidase (PHGPx), two proteins required for sperm maturation. Reduced PHGPx expression in apoER2 knockout mice results in the inability of the sperm to regulate the cell volume and in abnormal sperm morphology and immotility. Because insufficient expression of PHGPx is a major cause of infertility in men, these findings not only highlight an important new function for apoER2 that is unrelated to neuronal migration, but they also suggest a possible role for apoER2 in human infertility.Apolipoprotein (apo) E receptor-2 (apoER2) 1 is a member of the low density lipoprotein (LDL) receptor gene family and a prototype receptor that acts both in endocytosis and in signal transduction (1-4). In particular, apoER2 functions as a cellular receptor for Reelin, a signaling factor that regulates neuronal migration processes in the embryonic brain. Reelin binds to apoER2 and to the related very low density lipoprotein receptor on the surface of post-mitotic neurons that migrate to their proper position in the developing brain (2, 5). Binding of Reelin results in tyrosine phosphorylation of Disabled 1, an adaptor protein bound to the receptor tails, and in activation of downstream signaling pathways involving the Src family of tyrosine kinases and phosphatidylinositol 3-kinase (4, 6 -8). Defects in these signaling cascades as in apoER-2-deficient mice cause abnormal layering of neurons in the cortex, hippocampus, and cerebellum (9).Aside from post-mitotic neurons in the brain, apoer2 transcripts are also abundant in the placenta, the ovaries, and the epididymis (1, 3, 10). The function of the receptor in these tissues, however, remains unclear. In the present study, we aimed at elucidating novel roles for apoER2 in tissues other than the brain. We focused our attention on the male reproductive system because apoER2 is highly expressed in the principal cells of the epididymis (3) and because receptor-deficient mice suffer from male infertility (9). Here we have identified a crucial role for the receptor in sperm maturation, in particular in the acquisition and development of sperm motility. EXPERIMENTAL PROCEDURESMaterials-The generation of apoER2-deficient mice has been described before (9). Because of male infertility, the line was bred in-house by mating of homozygous-deficient (apoer2 Ϫ/Ϫ ) females with males heterozygous for the receptor gene defect (apoer2 ϩ/Ϫ )...

Molecular biology of glutathione peroxidase 4: from genomic structure to developmental expression and neural function

“…An intriguing link has been shown for apolipoprotein E receptor 2 (apoER2) expression and GPx4 translation (Andersen et al, 2003). ApoER2 is a member of the lipoprotein receptor gene family and acts as an important regulator of neuronal migration.…”

“…In particular, apoER2 transduces signaling from the guidance molecule Reelin and provides positional information for developing cortical and cerebellar neurons (D'Arcangelo et al, 1995;Tissir and Goffinet, 2003). ApoER2 deletion thus causes massive brain formation defects, as well as male infertility, which has been related to decreased GPx4 expression (Andersen et al, 2003). Whether apoER2 and Reelin signaling regulate GPx4 expression in the brain and whether GPx4 expression is affected by apoER2 deletion, and hence could cause the phenotype, remain to be demonstrated.…”

LRP8 mediates Wnt/β-catenin signaling and controls osteoblast differentiation

“…(27) Besides the brain, LRP8 is also expressed abundantly in the placenta, the ovaries, and the epididymis. (27,(31)(32)(33) LRP8, as one of the cell-surface receptors for Reelin, functions as an important regulator of neuron migration in brain development. (34,35) Reelin signals through LRP8 or through very-low-density lipoprotein receptor (VLDLR), induces the interaction between LRP8 and adaptor protein Disabled-1 (Dab1) and tyrosine phosphorylation of Dab1, and further, results in the recruitment of phosphatidylinositol-3-kinase (PI3K) and GSK3b.…”

Depletion of Selenoprotein GPx4 in Spermatocytes Causes Male Infertility in Mice

“…In mice, severe selenium deficiency resulted in male infertility (23), and selenoprotein P-null male mice are infertile due to depletion of selenocysteine transport into the testis via apoE receptor 2 (apoER2) (23,24). ApoER2-null mice also exhibited male infertility and a decrease in GPx4 expression in sperm (25).…”