Oligo‐astheno‐teratozoospermia in mice lacking ORP4, a sterol‐binding protein in the OSBP‐related protein family

Abstract

Oligo-astheno-teratozoospermia (OAT), a condition that includes low sperm number, low sperm motility and abnormal sperm morphology, is the commonest cause of male infertility. Because genetic analysis is frequently impeded by the infertility phenotype, the genetic basis of many of OAT conditions has been hard to verify. Here, we show that deficiency of ORP4, a sterol-binding protein in the oxysterol-binding protein (OSBP)-related protein family, causes male infertility due to severe OAT in mice. In ORP4-deficient mice, spermatogonia proliferation and subsequent meiosis occurred normally, but the morphology of elongating and elongated spermatids was severely distorted, with round-shaped head, curled back head or symplast. Spermatozoa derived from ORP4-deficient mice had little or no motility and no fertilizing ability in vitro. In ORP4-deficient testis, postmeiotic spermatids underwent extensive apoptosis, leading to a severely reduced number of spermatozoa. At the ultrastructural level, nascent acrosomes appeared to normally develop in round spermatids, but acrosomes were detached from the nucleus in elongating spermatids. These results suggest that ORP4 is essential for the postmeiotic differentiation of germ cells.

Oxysterol-binding Protein (OSBP)-related Protein 4 (ORP4) Is Essential for Cell Proliferation and Survival

“…A recent report that ORP4 knock-out mice are normal except for male infertility indicates that ORP4 has an essential function in tissues where it is highly expressed. In this case, lack of ORP4 resulted in apoptosis of postmeiotic spermatids and defects in germ cell differentiation (31). ORP4 could have an essential sterol and/or PI-4P transfer or sensing activity that has been re-established in immortalized and transformed cells to provide a growth advantage.…”

“…ORP4 is highly expressed in testis and, to a lesser extent, in brain and heart but is virtually absent from other human and mouse tissues (18,31). A recent report that ORP4 knock-out mice are normal except for male infertility indicates that ORP4 has an essential function in tissues where it is highly expressed.…”

ORP4L Facilitates Macrophage Survival via G-Protein–Coupled Signaling

“…Likewise, ORP4L deficiency did not affect the ability of macrophages to take up uncoated or ox-LDL-coated FluoSphere beads ( Figure 1D, middle) nor did it affect the engulfment of anti-Fas antibody-induced apoptotic Jurkat T cells ( Figure 1D, right). As ORP4 deletion has been reported to increase sperm apoptosis, 31 we next examined whether ORP4L modulates macrophage apoptosis. When compared with cells from WT mice, a significant increase in macrophage apoptosis was detected in preparations from ORP4L −/− mice ( Figure 1E).…”

“…[23][24][25][26] Certain ORPs bind and transport oxysterols, cholesterol, and phosphoinositides. [27][28][29] ORP4 (also known as oxysterol-binding protein 2) has been reported to bind oxysterols; it is expressed constitutively in brain, heart, and testis 30,31 and is present as 3 major variants, oxysterol-binding protein-related protein 4 L (ORP4L), ORP4M, and ORP4S. 30,32 Early studies reported that ORP4L was detectable in peripheral blood leukocytes from patients with chronic myeloid leukemia, but not from healthy donors.…”

“…35 ORP4 knockout mice exhibit sperm apoptosis, indicating that ORP4 is essential for the survival of specific cell types. 31 In this study, we investigate the role of ORP4L in macrophage survival and in the development of atherosclerotic lesions in mice.…”