Developmental activities of the complement pathway in migrating neurons

Gorelik, Anna; Sapir, Tamar; Haffner-Krausz, Rebecca; Olender, Tsviya; Woodruff, Trent M.; Reiner, Orly

doi:10.1038/ncomms15096

Cited by 102 publications

(101 citation statements)

References 44 publications

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“…In the healthy brain, complement proteins are expressed at relatively low levels and this expression vary with stages of maturation of neurons during neurodevelopment [14]. Neuronal migration is impaired in cases of ID, ASD, and schizophrenia, and complement pathway has been shown to be functionally important in migrating neurons of the developing cortex [12,36]. Abnormal levels of complement proteins have been linked to ASD [37].…”

Section: Discussionmentioning

confidence: 99%

“…Activation of the complement system has also been linked to obesity [10]. Moreover, dysregulation of complement has been demonstrated in both schizophrenia, bipolar disorders, and autism spectrum disorders (ASD), as involvement of the complement system in both synapse elimination and neuron migration in the developing brain has been recognized [11][12][13][14][15][16][17]. On the other hand, deficiency of complement components, including mannose-binding lectin (MBL), which is a part of lectin pathway, might increase the overall susceptibility to infectious disease [18].…”

Section: Introductionmentioning

confidence: 99%

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Complement Activation in 22q11.2 Deletion Syndrome

et al. 2020

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The 22q11.2 deletion syndrome (22q11.2 del), also known as DiGeorge syndrome, is a genetic disorder with an estimated incidence of 1:3000 to 1:6000 births. These patients may suffer from affection of many organ systems with cardiac malformations, immunodeficiency, hypoparathyroidism, autoimmunity, palate anomalies, and psychiatric disorders being the most frequent. The importance of the complement system in 22q11.2 del has not been investigated. The objective of this study was to evaluate the complement system in relation to clinical and immunological parameters in patients. A national cohort of patients (n = 69) with a proven heterozygous deletion of chromosome 22q11.2 and a group of age and sex matched controls (n = 56) were studied. Functional capacity of the classical, lectin, and alternative pathways of the complement system as well as complement activation products C3bc and terminal complement complex (TCC) were accessed and correlated to clinical features. All patients in our study had normal complement activation in both classical and alternative pathways. The frequency of mannose-binding lectin deficiency was comparable to the normal population. The patients had significantly raised plasma levels of C3bc and a slight, but not significant, increase in TCC compared with controls. This increase was associated with the presence of psychiatric disorders in patients. The present study shows no complement deficiencies in 22q11.2 deletion syndrome. On the contrary, there are signs of increased complement activation in these patients. Complement activation is particularly associated with the presence of psychiatric disorders.Journal of Clinical Immunology (2020) 40:515-523Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Complement Activation in 22q11.2 Deletion Syndrome

et al. 2020

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“…The brain itself secretes complement components which are critical to proper neurodevelopment. The lectin pathway by elaboration of C3a and C5a is very important in proper neuronal migration in the developing cortex [24]. …”

Section: Complement In Homeostasis and Pregnancymentioning

confidence: 99%

The Complement System and Preeclampsia

2017

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Purpose of review Preeclampsia affects 3–4% of pregnancies with few treatment options to reduce maternal and fetal harm. Recent evidence that targeting the complement system may be an effective therapeutic strategy in prevention or treatment of preeclampsia will be reviewed. Recent findings Studies in humans confirm the safety and efficacy of C5 blockade in complement-mediated disorders of pregnancy, including preeclampsia. Animal models mimic the placental abnormalities, and/or the maternal symptoms, which characterize preeclampsia. These models in mouse and rat have defined a role for complement and its regulators in placental dysfunction, hypertension, proteinuria, endothelial dysfunction, fetal growth restriction and angiogenic imbalance, thus informing future human studies. Summary Targeting excessive complement activation, particularly the terminal complement complex (C5b-9) and C5a may be an effective strategy to prolong pregnancy in women with preeclampsia. Continued research is needed to identify the initiator(s) of activation, the pathways involved and the key component(s) in the pathophysiology to allow development of safe and effective therapeutics to target complement without compromising its role in homeostasis and host defense.

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“…These include roles for complement factors in developmental processes such as radial intercalation, migration and synaptic pruning (Stevens et al 2007;Carmona-Fontaine et al 2011;Szabo et al 2016;Gorelik A et al 2017). In this context, it is…”

Section: Discussionmentioning

confidence: 99%

“…However, it is increasingly recognized that this evolutionarily ancient system also possesses unexpected roles in development, such as in morphogenesis, neurogenesis, migration, and neuronal synapse pruning Gorelik et al, 2017). Defects in complement signaling have been associated with neurodevelopmental abnormalities such as autism, schizophrenia, and 3MC syndrome (Corbett et al 2007; Despite these emerging developmental roles of complement, the functional role of C5aR1 in embryonic development remains poorly defined.…”

Section: Introductionmentioning

confidence: 99%

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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Developmental activities of the complement pathway in migrating neurons

Cited by 102 publications

References 44 publications

Complement Activation in 22q11.2 Deletion Syndrome

Complement Activation in 22q11.2 Deletion Syndrome

The Complement System and Preeclampsia

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

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