Complement 3 deficiency impairs early pregnancy in mice

Chow, Wang Ngai; Lee, Yin Lau; Wong, Po Chau; Chung, Man-Kin; Lee, Ckf; Yeung, William Shu Biu

doi:10.1002/mrd.21013

Cited by 42 publications

(42 citation statements)

References 44 publications

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“…Moderate C3 expression levels in mice are necessary for successful gestation because C3 knock-out (KO) animals have a much higher resorption rate 15 days post coitum than their WT counterparts, due to trophoblast dysfunction and labyrinth development defects [49]. Our in vitro experiments suggested that FOXD1 mutations decreasing or increasing C3 expression are deleterious.…”

Section: Discussionmentioning

confidence: 99%

Association of FOXD1 variants with adverse pregnancy outcomes in mice and humans

et al. 2016

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Recurrent spontaneous abortion (RSA) is a common cause of infertility, but previous attempts at identifying RSA causative genes have been relatively unsuccessful. Such failure to describe RSA aetiological genes might be explained by the fact that reproductive phenotypes should be considered as quantitative traits resulting from the intricate interaction of numerous genetic, epigenetic and environmental factors. Here, we studied an interspecific recombinant congenic strain (IRCS) of Mus musculus from the C57BL6/J strain of mice harbouring an approximate 5 Mb DNA fragment from chromosome 13 from Mus spretus mice (66H-MMU13 strain), with a high rate of embryonic resorption (ER). Transcriptome analyses of endometrial and placental tissues from these mice showed a deregulation of many genes associated with the coagulation and inflammatory response pathways. Bioinformatics approaches led us to select Foxd1 as a candidate gene potentially related to ER and RSA. Sequencing analysis of Foxd1 in the 66H-MMU13 strain, and in 556 women affected by RSA and 271 controls revealed non-synonymous sequence variants. In vitro assays revealed that some led to perturbations in FOXD1 transactivation properties on promoters of genes having key roles during implantation/placentation, suggesting a role of this gene in mammalian implantation processes.

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Section: Discussionmentioning

confidence: 99%

Association of FOXD1 variants with adverse pregnancy outcomes in mice and humans

et al. 2016

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“…In C3-knockout mice, C3 has been found to be needed for successful pregnancy. C3-knockout mice had a lower rate of conception and the fetal reabsorption rate was higher, while the fetal and placental weights were lower in these mice (8). Furthermore, in mice the C3-regulator Crry was found to be crucial to a successful pregnancy (9).…”

Section: Discussionmentioning

confidence: 95%

“…A well regulated C system is a prerequisite for a healthy pregnancy (8,9). Recently, mutations in C regulatory genes have been reported in women with recurrent pregnancy loss (10).…”

Section: Introductionmentioning

confidence: 99%

Complement activation and regulation in preeclamptic placenta

et al. 2014

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† Anna Inkeri Lokki and Jenni Heikkinen-Eloranta have contributed equally to this work.Preeclampsia (PE) is a common disorder of pregnancy originating in the placenta. We examined whether excessive activation or poor regulation of the complement system at the maternal-fetal interface could contribute to the development of PE. Location and occurrence of complement components and regulators in placentae were analyzed. Cryostat sections of placentae were processed from 7 early-onset PE (diagnosis <34 weeks of gestation), 5 late-onset PE, 10 control pregnancies, and immunostained for 6 complement activators and 6 inhibitors. Fluorescence was quantified and compared between PE and control placentae. Gene copy numbers of complement components C4A and C4B were assessed by a quantitative PCR method. Maternal C4 deficiencies (≥1 missing or nonfunctional C4) were most common in the early-onset PE group (71%), and more frequent in late-onset PE compared to healthy controls (60 vs. 38%). Complement C1q deposition differed significantly between control and patient groups: controls and early-onset PE patients had more C1q than late-onset PE patients (mean p = 0.01 and p = 0.005, respectively). C3 activation was analyzed by staining for C3b/iC3b and C3d. C3d was mostly specific to the basal syncytium and C3b/iC3b diffuse in other structures, but there were no clear differences between the study groups. Activated C4 and membrane-bound regulators CD55, CD46, and CD59 were observed abundantly in the syncytiotrophoblast. Syncytial knots, structures enriched in PE, stained specifically for the classical pathway inhibitor C4bp, whereas the key regulator alternative pathway, factor H (FH) showed a wider distribution in the placenta. Differences in C1q deposition between late-and early-onset PE groups may be indicative of the different etiology of PE symptoms in these patients. Irregular distribution of the complement regulators C4bp and FH in the PE placenta and a higher frequency of C4A deficiencies suggest a disturbed balance between complement activation and regulation in PE.

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“…Another recent paper showed that C3 has a physiological role in early phases of pregnancy; C3-knockout mice have smaller blastocysts, higher resorption rates and smaller sizes of placentae [11].…”

Section: Complement Activation In Healthy and Aps Pregnancymentioning

confidence: 98%