Cone-rod Homeobox CRX Controls Presynaptic Active Zone Formation in Photoreceptors of Mammalian Retina

Hum Mol Genet. 2018 Oct 15;27(20):3555-3567. doi: 10.1093/hmg/ddy272.

Abstract

In the mammalian retina, rod and cone photoreceptors transmit the visual information to bipolar neurons through highly specialized ribbon synapses. We have limited understanding of regulatory pathways that guide morphogenesis and organization of photoreceptor presynaptic architecture in the developing retina. While neural retina leucine zipper (NRL) transcription factor determines rod cell fate and function, cone-rod homeobox (CRX) controls the expression of both rod- and cone-specific genes and is critical for terminal differentiation of photoreceptors. A comprehensive immunohistochemical evaluation of Crx-/- (null), CrxRip/+ and CrxRip/Rip (models of dominant congenital blindness) mouse retinas revealed abnormal photoreceptor synapses, with atypical ribbon shape, number and length. Integrated analysis of retinal transcriptomes of Crx-mutants with CRX- and NRL-ChIP-Seq data identified a subset of differentially expressed CRX target genes that encode presynaptic proteins associated with the cytomatrix active zone (CAZ) and synaptic vesicles. Immunohistochemistry of Crx-mutant retina validated aberrant expression of REEP6, PSD95, MPP4, UNC119, UNC13, RGS7 and RGS11, with some reduction in Ribeye and no significant change in immunostaining of RIMS1, RIMS2, Bassoon and Pikachurin. Our studies demonstrate that CRX controls the establishment of CAZ and anchoring of ribbons, but not the formation of ribbon itself, in photoreceptor presynaptic terminals.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Cell Differentiation*
  • Disease Models, Animal
  • Eye Proteins / genetics*
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Leber Congenital Amaurosis / genetics
  • Leber Congenital Amaurosis / metabolism*
  • Leber Congenital Amaurosis / physiopathology
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins / genetics
  • Presynaptic Terminals
  • Retina / metabolism*
  • Retina / physiopathology
  • Retinal Cone Photoreceptor Cells / metabolism
  • Retinal Cone Photoreceptor Cells / physiology
  • Retinal Rod Photoreceptor Cells / metabolism
  • Retinal Rod Photoreceptor Cells / physiology
  • Signal Transduction*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*

Substances

  • Eye Proteins
  • Homeodomain Proteins
  • Nerve Tissue Proteins
  • Trans-Activators
  • cone rod homeobox protein