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

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.

Paralogous Genes Involved in Embryonic Development: Lessons from the Eye and other Tissues

“…Additive functions lead to a gradually worsened phenotype with a gradually decreased number of functional alleles of paralogous genes. A gradually decreased number of functional Dlx5/6 alleles leads to a gradually worsened craniofacial morphogenesis [ 84 ]; gradually reduced Onecut1/Onecut2 alleles cause a dramatically reduced number of horizontal cells in the mouse retina [ 62 ]; a gradually decreased number of functional Hoxa10 , Hoxc10 , and Hoxd10 alleles results in gradually worsened kidney development [ 85 ]; and a decreased number of Lef / Tcf alleles gradually alters the specification and maintenance of epithelial progenitor cells [ 69 ]. The threshold level of functional alleles is specific for particular tissues and organs, and may differ for individual paralogous genes.…”

“…A decline below the threshold level results in dramatic phenotypic consequences. The loss of more than one functional Dlx5/Dlx6 allele leads to alterations in pharyngeal patterning [ 84 ], a single Onecut1 / Onecut2 allele in any combination is not sufficient to prevent the complete loss of horizontal cells [ 62 ], less than three functional Hoxa10/Hoxc10/Hoxd10 alleles leads to defects during kidney development [ 85 ], and the presence of less than two out of the four Lef/Tcf transcription factors results in defects during lung development [ 69 ]. Additive functions were mostly observed for functionally equivalent paralogous genes, but non-equivalent paralogous genes may also exhibit additive functions.…”

“…Lack of two Onecut1/Onecut2 alleles in the mouse retina causes a dramatically decreased number of horizontal cells in any combination. One remaining Onecut1 or Onecut2 allele, similarly to the combined loss of Onecut1 together with Onecut2 , results in complete loss of horizontal cells [ 62 ]. ( c ) A synergistic interaction results in a mutant phenotype that exceeds expectations from observations of single knockouts.…”

“…A lack of three or all four alleles results in the complete loss of horizontal cells. Therefore, only one functional Onecut1 or Onecut2 allele is not able to rescue the phenotype, and the horizontal cells will be depleted [ 62 ].…”

A Single Cell Genomics Atlas of theDrosophilaLarval Eye Reveals Distinct Developmental Timelines and Novel Markers for All Photoreceptor Subtypes

“…Our snATAC-seq motif analyses using the JASPAR and i-cisTarget databases 53,61 also show Onecut motif enrichment in the Convergence cluster. onecut is highly conserved and required for horizontal cell development in mice [62][63][64] . In Drosophila, we have found that onecut null mutants show age-related retinal dysmorphology with loss of PR rhabdomeres (to be reported elsewhere).…”