Complement C3a receptor modulates embryonic neural progenitor cell proliferation and cognitive performance

Complement System in Brain Architecture and Neurodevelopmental Disorders

“…These findings were further corroborated by an in vitro study using NPC isolated from adult mouse brain showing that C3a stimulates their neuronal differentiation without altering their survival and proliferation (Shinjyo et al, 2009; Table 1). Consistent with the findings that C3a/C3aR signaling regulates neurogenesis, adult C3aR knockout mice show deficits in memory (Coulthard et al, 2018a).…”

“…It is noteworthy, however, that an opposite trend was observed for C3aR knockout mouse embryos, that display decreased proliferation of NPC within the ventricular zone (Coulthard et al, 2018a; Table 1). This discrepancy between the use of C3aR pharmacological blocker and C3aR knockout may be attributed in part to combinatorial modulation of other signaling pathways in the absence of C3aR during the entire developmental period (Coulthard et al, 2018a). In the context of adult mouse brain, previous studies have shown that young adult mice lacking C3, C3aR or treated with C3aR antagonist exhibit reduced neurogenesis from NPC in the neurogenic niches, possibly due to impaired NPC differentiation rather than decreased proliferation of these cells (Rahpeymai et al, 2006).…”

“…It has recently been shown that mouse embryos deficient for C3, Masp2 or treated with C3aR antagonist exhibit increased proliferation of NPC in the brain ventricular or subventricular zones, suggesting that these complement components inhibit NPC proliferation at early stages of cortical development (Gorelik et al, 2017a;Coulthard et al, 2018a). It is noteworthy, however, that an opposite trend was observed for C3aR knockout mouse embryos, that display decreased proliferation of NPC within the ventricular zone (Coulthard et al, 2018a; Table 1). This discrepancy between the use of C3aR pharmacological blocker and C3aR knockout may be attributed in part to combinatorial modulation of other signaling pathways in the absence of C3aR during the entire developmental period (Coulthard et al, 2018a).…”

“…Constitutive deficiency of C5aR and acute pharmacological blockade of C5aR during neurogenesis also caused opposing phenotypes of NPC proliferation. While the use of C5aR antagonist inhibits NPC proliferation in the ventricular zone of mouse embryos and lead to brain microstructural alterations and behavioral deficits (such as heightened anxiety, impaired coordination, and short-term memory) later in life (Coulthard et al, 2017), C5aR knockout mice exhibit increased proliferation of NPC within the ventricular zone (Coulthard et al, 2018a; Table 1). In addition, while in the postnatal rat cerebellar cortex a C5aR agonist was shown to stimulate proliferation of immature granule neurons, which suggests a role for the C5a-C5aR axis in the cerebellar histogenesis (Benard et al, 2008), C5a-C5aR1 signaling seems not to be involved in NPC proliferation and differentiation in the neurogenic niches of the adult brain (Bogestal et al, 2007;Shinjyo et al, 2009; Table 1).…”

Pathological significance of C3aR signaling in the tumor cells of clear cell renal cell carcinoma: a clinical observation

“…However, increasing evidence from the last two decades has demonstrated that C3aR is also expressed by many non-immune cells and participates in various physiological and pathological processes. For examples, C3aR signaling was reported to participate in the regulation of eye morphogenesis [16], neural development [17][18], embryonic chick retina [19] and cardiac resident cell [20] regeneration, astroglial cell differentiation [21] and survival [22], diet-induced obesity and metabolic dysfunction [23], and tau hyperphosphorylation in Alzheimer's Disease [24]. Also, C3aR signaling was found to be involved in the induction of in ammatory cytokines [25], proliferation of mesangial [11] and carcinoma cells [12] and EMT of tubular epithelial cells [10].…”