Infertile Spermatozoa of c-ros Tyrosine Kinase Receptor Knockout Mice Show Flagellar Angulation and Maturational Defects in Cell Volume Regulatory Mechanisms1

Yeung, Ching‐Hei; Sonnenberg-Riethmacher, Eva; Cooper, Trevor G.

doi:10.1095/biolreprod61.4.1062

Cited by 140 publications

(136 citation statements)

References 34 publications

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“…Sperm with defective cell volume decrease fail to counteract water influx when released into hypo-osmotic conditions, causing cell swelling and coiling of the tail. The swelling is relieved upon perforation of the sperm membrane with detergents, resulting in tail straightness (20,21).…”

Section: Resultsmentioning

confidence: 99%

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

Andersen

Yeung²,

Vorum

et al. 2003

Journal of Biological Chemistry

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103

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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 )...

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Section: Resultsmentioning

confidence: 99%

“…The receptor tyrosine kinase c-Ros is an orphan receptor expressed in the initial segment and in the caput epididymis (46). Lack of the initial segment of the epididymis in c-Ros-deficient mice coincides with cell volume dysregulation (20,(47)(48)(49).…”

Section: Figmentioning

confidence: 99%

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

Andersen

Yeung²,

Vorum

et al. 2003

Journal of Biological Chemistry

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103

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“…The adverse effects of quinine on rodents have been investigated in many studies [9,[30][31][32][33][34][35][36] .…”

Section: Discussionmentioning

confidence: 99%

Comparative study of chloroquine and quinine on malaria rodents and their effects on the mouse testis

Abolghasemi

Moosa-Kazemi

Davoudi

et al. 2012

Asian Pacific Journal of Tropical Biomedicine

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“…C-ros oncogene 1 (Ros1) knockout male mice that lacked prepubertal differentiation of the epididymal initial segment were healthy but infertile (3). Spermatozoa from Ros1 knockouts showed flagellar angulation, a defect in sperm maturation (4). Therefore, it is important to examine the mechanisms by which the initial segment develops, functions normally, and contributes to normal sperm maturation.…”

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confidence: 99%

PTEN signaling through RAF1 proto-oncogene serine/threonine kinase (RAF1)/ERK in the epididymis is essential for male fertility

Washington

Hinton

2014

Proc. Natl. Acad. Sci. U.S.A.

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Without a fully developed initial segment, the most proximal region of the epididymis, male infertility results. Therefore, it is important to understand the development and regulation of this crucial region. In addition to distinctively high activity levels of the components of the ERK pathway, which are essential for initialsegment differentiation, the initial segment exhibits high protein and activity levels of phosphatase and tensin homolog (PTEN). To understand the role of PTEN in the regulation of the initial segment, we generated a mouse model with a conditional deletion of Pten from the epithelial cells of the proximal epididymis from postnatal day 17 (P17) onward. Shortly after Pten deletion, hypertrophy of the proximal epididymis became evident. Loss of Pten resulted in activation of the AKT (protein kinase B) pathway components from P28 onward, which in turn gradually suppressed RAF1 proto-oncogene serine/threonine kinase (RAF1)/ERK signaling through the interaction between AKT and RAF1. Consistent with progressive changes in RAF1/ERK signaling, loss of Pten progressively altered cell shape, size, organization, proliferation, and survival in the initial-segment epithelium and resulted in dedifferentiation and extensive epithelial folding. Most importantly, knockout males progressively lost fertility and became infertile from 6 to 12 mo. Spermatozoa from older knockout mice showed a lower percentage of motility and a higher percentage of flagellar angulation compared with controls, suggesting compromised sperm maturation. Therefore, under normal physiological conditions, PTEN suppresses AKT activity to maintain activation of the RAF1/ERK signaling pathway, which in turn maintains normal function of the initial segment and therefore, normal sperm maturation.S permatozoa enter the epididymis from the testes as immotile cells that are incapable of fertilization. During epididymal transit, a complex process called sperm maturation allows for conversion of spermatozoa into motile and fertilization-competent cells. The long, convoluted epididymal duct-which is ∼6 m long in humans and 1 m in mice (1)-provides a luminal fluid microenvironment that is necessary for sperm maturation (2).It is apparent that the most proximal region of the epididymis, the initial segment, plays an important role in sperm maturation. C-ros oncogene 1 (Ros1) knockout male mice that lacked prepubertal differentiation of the epididymal initial segment were healthy but infertile (3). Spermatozoa from Ros1 knockouts showed flagellar angulation, a defect in sperm maturation (4). Therefore, it is important to examine the mechanisms by which the initial segment develops, functions normally, and contributes to normal sperm maturation.The initial segment exhibits high activity levels of the ERK pathway components. The ERK pathway [also known as the RAF (RAF proto-oncogene serine/threonine kinases)/MEK/ERK pathway] is an intracellular protein kinase cascade containing at least MAPK3 and/or MAPK1 (commonly known as ERK1 and ERK2), a MAPKK (com...

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Infertile Spermatozoa of c-ros Tyrosine Kinase Receptor Knockout Mice Show Flagellar Angulation and Maturational Defects in Cell Volume Regulatory Mechanisms1

Cited by 140 publications

References 34 publications

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

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

Comparative study of chloroquine and quinine on malaria rodents and their effects on the mouse testis

PTEN signaling through RAF1 proto-oncogene serine/threonine kinase (RAF1)/ERK in the epididymis is essential for male fertility

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