Abstract
During development, neurons generate excess processes which are then eliminated in concert with circuit maturation. C1q is the initiating protein in the complement cascade and has been implicated in this process, but whether C1q-mediated elimination is targeted to particular neural compartments is unclear. Using the murine retina, we identify C1q as a specific regulator of horizontal cell neurite confinement. Subsets of horizontal cell dendritic and axonal neurites extend into the outer retina suggesting that complement achieves both cellular and subcellular selectivity. These alterations emerge as outer retina synapses become mature. C1q expression is restricted to retina microglia, and the loss of C1q results in decreased microglia activation. This pathway appears independent of the C3a receptor (C3aR) and complement receptor 3 (CR3), as horizontal cells are normal when either protein is absent. Together, these data identify a new role for C1q in cell and neurite-specific confinement and implicate microglia-mediated phagocytosis in this process.
Highlights
IntroductionWork over the past 15 years has established that the central nervous system (CNS) can leverage complement to control synapse elimination during development and disease (Stevens et al, 2007; Chu et al, 2010; Bialas and Stevens, 2013; Hong et al, 2016)
The complement pathway is comprised of over 20 innate immune signaling proteins
Horizontal cells failed to remain confined to the outer plexiform layer (OPL) at P13 in C1q−/− mice, extending numerous long neurites into the outer retina (Figure 1B)
Summary
Work over the past 15 years has established that the central nervous system (CNS) can leverage complement to control synapse elimination during development and disease (Stevens et al, 2007; Chu et al, 2010; Bialas and Stevens, 2013; Hong et al, 2016). Deletion of C1q, the initiating complement pathway signaling molecule, results in delayed refinement of the dorsolateral geniculate nucleus of the thalamus and causes defects in the development of spinal motor circuits through altered microglia-mediated removal of excess neurites and synapses (Stevens et al, 2007; Vukojicic et al, 2019). C1q-mediated synapse removal has been implicated in Alzheimer’s disease and in cognitive defects following neurotropic virus infection (Hong et al, 2016; Kunnakkadan et al, 2019). C1q may target particular neuronal circuits or even specific neuron or synapse types for elimination
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