title: Investigation of retinoic acid function during embryonic brain development using retinaldehyde-rescued Rdh10 knockout mice.
abstract: BACKGROUND
  Retinoic acid (RA) signaling controls patterning and neuronal differentiation within the hindbrain, but forebrain RA function remains controversial. RA is produced from metabolism of retinol to retinaldehyde by retinol dehydrogenase (RDH), followed by metabolism of retinaldehyde to RA by retinaldehyde dehydrogenase (RALDH). Previous studies on Raldh2-/- and Raldh3-/- mice demonstrated an RA requirement for γ-aminobutyric acid (GABA)ergic and dopaminergic differentiation in forebrain basal ganglia, but no RA requirement was observed during early forebrain patterning or subsequent forebrain cortical expansion. However, other studies suggested that RA controls forebrain patterning, and analysis of ethylnitrosourea-induced Rdh10 mutants suggested that RA synthesized in the meninges stimulates forebrain cortical expansion.
  
  
  RESULTS
  We generated Rdh10-/- mouse embryos that lack RA activity early in the head and later in the meninges. We observed defects in hindbrain patterning and eye RA signaling, but early forebrain patterning was unaffected. Retinaldehyde treatment of Rdh10-/- embryos from E7-E9 rescues a cranial skeletal defect, resulting in E14.5 embryos lacking meningeal RA activity but maintaining normal forebrain shape and cortical expansion.
  
  
  CONCLUSIONS
  Rdh10-/- embryos demonstrate that RA controls hindbrain but not early forebrain patterning, while studies on retinaldehyde-rescued Rdh10-/- embryos show that meningeal RA synthesis is unnecessary to stimulate forebrain cortical expansion.
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Chatzi
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Cunningham
authors.forename: Gregg
authors.initials: G
authors.lastname: Duester
mesh_terms: D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology*; D005123:Eye / Q000166:cytology / Q000196:embryology; D051379:Mice; D018345:Mice, Knockout; D055495:Neurogenesis / Q000502:physiology*; D016548:Prosencephalon / Q000166:cytology / Q000196:embryology*; D012172:Retinaldehyde / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D014212:Tretinoin; D000429:Alcohol Oxidoreductases; C113992:trans-retinol dehydrogenase; D012172:Retinaldehyde
keywords: Rdh10 knockout; cortex; forebrain; hindbrain; meninges; retinaldehyde; retinoic acid