Cutting Edge: Inhibiting Measles Virus Infection but Promoting Reproduction: An Explanation for Splicing and Tissue-Specific Expression of CD46

Riley, Rebecca C.; Tannenbaum, Pamela L.; Abbott, David H.; Atkinson, John P.

doi:10.4049/jimmunol.169.10.5405

Cited by 32 publications

(31 citation statements)

References 29 publications

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“…However, several molecularly engineered mice already developed to study the function of complement regulatory proteins, including two mDAF knockout mice (40), and mCd59a-(33) and S-proteindeficient mice (41) did not show any major fertility problem. Several in vitro studies suggested a role for MCP in sperm-egg interaction (42), but the targeted deletion of mouse MCP did not affect their reproductive efficacy (43). Together, these studies illustrate that in mice, DAF, mCd59a, MCP, and S-protein are not individually essential for fetal development/survival or for protecting sperm from complement activation in the male or the female reproductive system.…”

Section: ) C Complement Activity In Mcd59bmentioning

confidence: 71%

Further Characterization of Reproductive Abnormalities in mCd59b Knockout Mice: A Potential New Function of mCd59 in Male Reproduction

Qin

Dobarro

Bedford

et al. 2005

The Journal of Immunology

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CD59 is a GPI-linked membrane protein that inhibits formation of the membrane attack complex of complement. We reported recently that mice have two CD59 genes (termed mCd59a and mCd59b), and that the targeted deletion of mCd59b (mCd59b−/−) results in spontaneous hemolytic anemia and progressive loss of male fertility. Further studies of the reproductive abnormalities in mCd59b−/− mice reported in this study revealed the presence of abnormal multinucleated cells and increased apoptotic cells within the walls of the seminiferous tubules, and a decrease in the number, motility, and viability of sperm associated with a significant increase in abnormal sperm morphologies. Both the capacitation-associated tyrosine phosphorylation and the ionophore-induced acrosome reaction as well as luteinizing hormone, follicle-stimulating hormone, and testosterone serum levels were similar in mCd59b−/− and mCd59b+/+. Surprisingly, the functional deficiency of the complement protein C3 did not rescue the abnormal reproductive phenotype of mCd59b−/−, although it was efficient in rescuing their hemolytic anemia. These results indicate that the male reproductive abnormalities in mCd59b−/− are complement-independent, and that mCd59 may have a novel function in spermatogenesis that is most likely unrelated to its function as an inhibitor of membrane attack complex formation.

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Section: ) C Complement Activity In Mcd59bmentioning

confidence: 71%

Further Characterization of Reproductive Abnormalities in mCd59b Knockout Mice: A Potential New Function of mCd59 in Male Reproduction

Qin

Dobarro

Bedford

et al. 2005

The Journal of Immunology

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“…However, the loss of this repeat does not affect MCP's complement-regulatory ability (33)(34)(35). Surprisingly, New World monkeys retain expression of CCP1 on spermatozoa (32). This conservation of structure suggests that MCP participates in fertilization, in addition to being a complement regulator.…”

Section: Introductionmentioning

confidence: 99%

“…First, as noted, the retention of CCP1 on spermatozoa of New World monkeys and the Ab inhibition data both suggest that CCP1 might be playing a role in fertilization independent of complement activation (32). Second, in 1993 Anderson et al described a model whereby MCP might be one half of a C3b dimer bridge between the spermatozoa and the egg (29).…”

Section: Introductionmentioning

confidence: 99%

“…In particular, Abs against complement control protein repeat 1 (CCP1), the aminoterminal CCP, block binding more efficiently than function-blocking Abs that bind to CCPs 3 and 4 (30). This observation led us to evaluate MCP expression on spermatozoa of New World monkeys (32), since they express a splice alternative of MCP lacking CCP1 on somatic cells (33). This variant may protect against infection by measles virus, whose hemagglutinin requires CCP1 to bind MCP (33).…”

Section: Introductionmentioning

confidence: 99%

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Targeted and restricted complement activation on acrosome-reacted spermatozoa

Riley-Vargas¹,

Lanzendorf²,

Atkinson³

2005

J. Clin. Invest.

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A specific hypoglycosylated isoform of the complement regulator membrane cofactor protein (MCP; CD46) is expressed on the inner acrosomal membrane (IAM) of spermatozoa. This membrane is exposed after the acrosome reaction, an exocytosis event that occurs upon contact with the zona pellucida. We initiated this investigation to assess MCP's regulatory function in situ on spermatozoa. Upon exposure of human spermatozoa to autologous serum or follicular fluid, we unexpectedly observed that acrosome-reacted spermatozoa activated the complement cascade efficiently through C3 but not beyond. Using FACS to simultaneously evaluate viability, acrosomal status, and complement deposition, we found that complement activation was initiated by C-reactive protein (CRP) and was C1q, C2, and factor B dependent. This pattern is consistent with engagement of the classical pathway followed by amplification through the alternative pathway. C3b deposition was targeted to the IAM, where it was cleaved to C3bi. Factor H, and not MCP, was the cofactor responsible for C3b cleavage. We propose that this localized deposition of complement fragments aids in the fusion process between the spermatozoa and egg, in a role akin to that of complement in immune adherence. In addition, we speculate that this "targeted and restricted" form of complement activation on host cells is a common strategy to handle modified self.

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“…is not through traditional C3b binding, but through an alternative binding domain CCP1 which is selectively expressed in the testes of these animals (Riley et al 2002b). In support of this, CCP1…”

Section: Adhesionmentioning

confidence: 71%

Exploring the role of C5a-C5aR1 signalling in development through pluripotent stem cell modelling

Hawksworth¹

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The complement system has been traditionally described as a powerful controller of innate immunity.With activation through the recognition of pathogenic surfaces, spontaneous hydrolysis, or extrinsic cleavage, a cleavage cascade is initiated culminating in the formation of the active complement fragments C3a, C3b, C5a, and C5b. These fragments direct immune cells to sites of inflammation, as well as tagging pathogens for destruction and directly lysing foreign cells. It is now clear however, that this complex family of proteins possesses a wide range of functions outside of immune regulation. From fertilisation and morphogenesis, to the control of foetal and adult stem cell populations, studies have described novel actions of complement factors. This thesis is focussed on the central complement receptor, C5aR1. Traditionally described as a potent activating and chemotactic receptor for immune cells, C5aR1 has been shown to function in a number of nonimmune cell populations. Of note, our laboratory has previously described a role for C5aR1 in neural tube closure, with loss of C5aR1 signalling associated with increased neural tube defects under folate deficient conditions. However, a mechanistic role of C5aR1 at this stage of development was not described.In this thesis, pluripotent stem cells were utilised as an in vitro model of human development to interrogate the expression and function of C5aR1 at a number of developmental stages. Specifically, in pluripotent stem cells representative of the blastocyst inner cell mass, in neural rosettes representative of the developing ventricular zone, and in matured post-mitotic cortical neurons. This builds on previous work by our laboratory, which had identified C5aR1 actions in the mouse ventricular zone, analogous to late neural rosette cultures, and had shown a neurotoxic effect of C5aR1 in post-mitotic mouse neurons.C5aR1 was found to be expressed in pluripotent stem cells, with a role in promoting maintenance of pluripotency in the absence of FGF2 signalling. Additionally, C5aR1 was found to be apically expressed in human neural rosettes, with signalling promoting proliferation and maintenance of cell polarity. This work correlated well with mouse studies performed outside of this thesis, to show that in vivo, loss of C5aR1 in this neural progenitor population resulted in behavioural deficits and microstructural brain changes. Lastly, we determined the mRNA expression of C5aR1 in human postmitotic cortical neurons. However, in contrast to previous mouse studies, exogenous C5a, alone or in the presence of secondary stressors, had little effect on the survival of these cells.Overall, the results presented in this thesis have further expanded our knowledge of C5a-C5aR1 signalling in development, describing novel roles for this signalling pathway. The use of pluripotent stem cells allowed for the exploration of C5aR1 actions in human development that would otherwise be limited to animal models. Additionally, it allowed for the correlation of previous animal resu...

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Cutting Edge: Inhibiting Measles Virus Infection but Promoting Reproduction: An Explanation for Splicing and Tissue-Specific Expression of CD46

Cited by 32 publications

References 29 publications

Further Characterization of Reproductive Abnormalities in mCd59b Knockout Mice: A Potential New Function of mCd59 in Male Reproduction

Further Characterization of Reproductive Abnormalities in mCd59b Knockout Mice: A Potential New Function of mCd59 in Male Reproduction

Targeted and restricted complement activation on acrosome-reacted spermatozoa

Exploring the role of C5a-C5aR1 signalling in development through pluripotent stem cell modelling

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