Dose-dependent regulation of horizontal cell fate by Onecut family of transcription factors

PLoS One. 2020 Aug 13;15(8):e0237403. doi: 10.1371/journal.pone.0237403. eCollection 2020.

Abstract

Genome duplication leads to an emergence of gene paralogs that are essentially free to undergo the process of neofunctionalization, subfunctionalization or degeneration (gene loss). Onecut1 (Oc1) and Onecut2 (Oc2) transcription factors, encoded by paralogous genes in mammals, are expressed in precursors of horizontal cells (HCs), retinal ganglion cells and cone photoreceptors. Previous studies have shown that ablation of either Oc1 or Oc2 gene in the mouse retina results in a decreased number of HCs, while simultaneous deletion of Oc1 and Oc2 leads to a complete loss of HCs. Here we study the genetic redundancy between Oc1 and Oc2 paralogs and focus on how the dose of Onecut transcription factors influences abundance of individual retinal cell types and overall retina physiology. Our data show that reducing the number of functional Oc alleles in the developing retina leads to a gradual decrease in the number of HCs, progressive thinning of the outer plexiform layer and diminished electrophysiology responses. Taken together, these observations indicate that in the context of HC population, the alleles of Oc1/Oc2 paralogous genes are mutually interchangeable, function additively to support proper retinal function and their molecular evolution does not follow one of the typical routes after gene duplication.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Amacrine Cells / metabolism
  • Amacrine Cells / pathology
  • Animals
  • Ependymoglial Cells / metabolism
  • Ependymoglial Cells / pathology
  • Eye / growth & development
  • Eye / pathology
  • Genetic Loci
  • Genotype
  • Hepatocyte Nuclear Factor 6 / genetics*
  • Hepatocyte Nuclear Factor 6 / metabolism
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Mice
  • Mice, Transgenic
  • Retina / cytology
  • Retina / pathology
  • Retina / physiology*
  • Retinal Bipolar Cells / metabolism
  • Retinal Bipolar Cells / pathology
  • Retinal Cone Photoreceptor Cells / metabolism
  • Retinal Cone Photoreceptor Cells / pathology
  • Retinal Ganglion Cells / cytology
  • Retinal Ganglion Cells / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism

Substances

  • Hepatocyte Nuclear Factor 6
  • Homeodomain Proteins
  • ONECUT2 protein, mouse
  • Onecut1 protein, mouse
  • Transcription Factors

Grants and funding

This work was supported by GACR 18-20759S (awarded to ZK) and by Deutsche Forschungsgemeinschaft Grant FOR 1075 (TPZ) awarded to HJ. Research on animal models is supported by RVO68378050-KAV-NPUI (awarded to ZK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.