TGF-β signaling regulates neuronal C1q expression and developmental synaptic refinement

Nat Neurosci. 2013 Dec;16(12):1773-82. doi: 10.1038/nn.3560. Epub 2013 Oct 27.

Abstract

Immune molecules, including complement proteins C1q 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 C1q, the initiating protein of the classical complement cascade, during retinogeniculate refinement; however, the signals controlling C1q expression and function remain elusive. Previous work implicated an astrocyte-derived factor in regulating neuronal C1q expression. Here we identify retinal transforming growth factor (TGF)-β as a key regulator of neuronal C1q expression and synaptic pruning in the developing visual system. Mice lacking TGF-β receptor II (TGFβRII) in retinal neurons had reduced C1q 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-β in regulating neuronal C1q expression to initiate complement- and microglia-mediated synaptic pruning.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Animals, Newborn
  • Cell Count
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Complement C1q / genetics
  • Complement C1q / metabolism*
  • Gene Expression Regulation, Developmental / drug effects
  • Gene Expression Regulation, Developmental / physiology*
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Homeodomain Proteins / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neuroglia / chemistry
  • Neuroglia / physiology
  • Protein-Serine-Threonine Kinases / deficiency
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / deficiency
  • Retina / cytology
  • Retina / drug effects
  • Retina / growth & development
  • Retina / metabolism
  • Retinal Ganglion Cells / drug effects
  • Retinal Ganglion Cells / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Synapses / drug effects
  • Synapses / physiology*
  • Transcription Factors / genetics
  • Transforming Growth Factor beta / metabolism*

Substances

  • Homeodomain Proteins
  • Receptors, Transforming Growth Factor beta
  • Transcription Factors
  • Transforming Growth Factor beta
  • Vsx2 protein, mouse
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • Complement C1q
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II