MHC Receptor for Retinal Circuitry

Science Signaling  02 Mar 2010:
Vol. 3, Issue 111, pp. ec66
DOI: 10.1126/scisignal.3111ec66

Molecules previously associated with immune function are emerging as regulators of the nervous system as well. CD3ζ, a molecule best known for its role as a subunit of the T cell receptor complex, participates in the binding of major histocompatibility complex class I (MHC I). Genetic knockout studies indicate that MHC I and CD3ζ are important for neuron plasticity, as well as activity-dependent synaptic development, such as those controlling vision [specifically, the projection of the retinal ganglion cells (RGCs) into the dorsal lateral geniculate nucleus (dLGN)]. Xu et al. follow up on this retinal development defect of CD3ζ-deficient mice. They established that CD3ζ was present in the RGCs (mRNA and protein). In vivo monitoring of RGCs labeled by expression of genetically encoded yellow fluorescent protein showed that CD3ζ-knockout mice had increased numbers and densities of dendritic protrusions than did age-matched controls, both at early times after birth and in adults. Time-lapse microscopy showed that the RGCs had reduced dendritic motility, which was associated with an increased lifetime of dendritic protrusions. Because of the increased dendritic density, the CD3ζ-knockout mice failed to segregate their RGC connections properly, with RGCs extending into more than one layer of the inner plexiform layer and thus receiving input from both the cells that respond to the onset of light, as well as those that respond to the offset of light, instead of from only one or the other as occurs in wild-type mice. Whereas cholinergic activity controls RGC activity in the first week after birth, glutamatergic signaling controls RGC activity thereafter. Retinal wave activity within the first week after birth (mediated by acetylcholine receptors) was normal in the retinas of the CD3ζ-knockout mice, whereas by 10 days after birth retinal wave activity was reduced in the CD3ζ-knockout mice. Pharmacological blockade of glutamate receptor signaling phenocopied the RGC projection defects observed in CD3ζ-knockout mice but failed to cause any additional reduction in dendritic motility or increase in dendritic density when injected into the eyes of CD3ζ-knockout mice. Thus, CD3ζ is important for glutamatergic synaptic activity that controls retinal development. The exact mechanism by which CD3ζ contributes to glutamatergic signaling remains to be determined (see Higenell and Ruthazer).

H.-p. Xu, H. Chen, Q. Ding, Z.-H. Xie, L. Chen, L. Diao, P. Wang, L. Gan, M. C. Crair, N. Tian, The immune protein CD3ζ is required for normal development of neural circuits in the retina. Neuron 65, 503–515 (2010). [Online Journal]

V. Higenell. E. S. Ruthazer, Layers upon layers: MHC class I acts in the retina to influence thalamic segregation. Neuron 65, 439–441 (2010). [Online Journal]