Neural retina-specific Aldh1a1 controls dorsal choroidal vascular development via Sox9 expression in retinal pigment epithelial cells

Elife. 2018 Apr 3;7:e32358. doi: 10.7554/eLife.32358.

Abstract

VEGF secreted from retinal pigment epithelial (RPE) cells is responsible for the choroidal vascular development; however, the molecular regulatory mechanism is unclear. We found that Aldh1a1-/- mice showed choroidal hypoplasia with insufficient vascularization in the dorsal region, although Aldh1a1, an enzyme that synthesizes retinoic acids (RAs), is expressed in the dorsal neural retina, not in the RPE/choroid complex. The level of VEGF in the RPE/choroid was significantly decreased in Aldh1a1-/- mice, and RA-dependent enhancement of VEGF was observed in primary RPE cells. An RA-deficient diet resulted in dorsal choroidal hypoplasia, and simple RA treatment of Aldh1a1-/- pregnant females suppressed choroid hypoplasia in their offspring. We also found downregulation of Sox9 in the dorsal neural retina and RPE of Aldh1a1-/- mice and RPE-specific disruption of Sox9 phenocopied Aldh1a1-/- choroidal development. These results suggest that RAs produced by Aldh1a1 in the neural retina directs dorsal choroidal vascular development via Sox9 upregulation in the dorsal RPE cells to enhance RPE-derived VEGF secretion.

Keywords: Aldh1a1; Sox9; VEGF; choroid; developmental biology; mouse; neuroscience; retinal pigment epithelium; retinoic acid; stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Dehydrogenase / genetics
  • Aldehyde Dehydrogenase / metabolism*
  • Aldehyde Dehydrogenase 1 Family
  • Animals
  • Choroid / physiology*
  • Epithelial Cells / physiology
  • Gene Expression Regulation*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neovascularization, Physiologic*
  • Retinal Dehydrogenase
  • Retinal Pigment Epithelium / physiology*
  • SOX9 Transcription Factor / metabolism*
  • Tretinoin / metabolism
  • Vascular Endothelial Growth Factor A / metabolism*

Substances

  • SOX9 Transcription Factor
  • Sox9 protein, mouse
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • Tretinoin
  • Aldehyde Dehydrogenase 1 Family
  • Aldehyde Dehydrogenase
  • ALDH1A1 protein, mouse
  • Retinal Dehydrogenase

Grant support

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.