TGF-β signaling regulates neuronal Clq expression and developmental synaptic refinement

Immune molecules, including complement proteins Clq and C3, have emerged as critical mediators of synaptic refinement and plasticity. Complement localizes to synapses and refines the developing visual system through C3-dependent microglial phagocytosis of synapses. Retinal ganglion cells (RGCs) express Clq, the initiating protein of the classical complement cascade, during retinogeniculate refinement; however, the signals controlling Clq expression and function remain elusive. Previous work implicated an astrocyte-derived factor in regulating neuronal Clq expression. Here we identify retinal transforming growth factor (TGF)-beta as a key regulator of neuronal Clq expression and synaptic pruning in the developing visual system. Mice lacking TGF-beta receptor II (TGF beta R11) in retinal neurons had reduced Clq expression in RGCs and reduced synaptic localization of complement, and phenocopied refinement defects observed in complement-deficient mice, including reduced eye-specific segregation and microglial engulfment of RGC inputs. These data implicate TGF-beta in regulating neuronal Clq expression to initiate complement- and microglia-mediated synaptic pruning.