title: A zebrafish model of axenfeld-rieger syndrome reveals that pitx2 regulation by retinoic acid is essential for ocular and craniofacial development.
abstract: OBJECTIVE
  The homeobox transcription factor PITX2 is a known regulator of mammalian ocular development, and human PITX2 mutations are associated with Axenfeld-Rieger syndrome (ARS). However, the treatment of patients with ARS remains mostly supportive and palliative.
  
  
  METHODS
  The authors used molecular genetic, pharmacologic, and embryologic techniques to study the biology of ARS in a zebrafish model that uses transgenes to mark neural crest and muscle cells in the head.
  
  
  RESULTS
  The authors demonstrated in vivo that pitx2 is a key downstream target of retinoic acid (RA) in craniofacial development, and this pathway is required for coordinating neural crest, mesoderm, and ocular development. pitx2a knockdown using morpholino oligonucleotides disrupts jaw and pharyngeal arch formation and recapitulates ocular characteristics of ARS, including corneal and iris stroma maldevelopment. These phenotypes could be rescued with human PITX2A mRNA, demonstrating the specificity of the knockdown and evolutionary conservation of pitx2a function. Expression of the ARS dominant negative human PITX2A K50E allele also caused ARS-like phenotypes. Similarly, inhibition of RA synthesis in the developing eye (genetic or pharmacologic) disrupted craniofacial and ocular development, and human PITX2A mRNA partially rescued these defects.
  
  
  CONCLUSIONS
  RA regulation of pitx2 is essential for coordinating interactions among neural crest, mesoderm, and developing eye. The marked evolutionary conservation of Pitx2 function in eye and craniofacial development makes zebrafish a potentially powerful model of ARS, amenable to in vivo experimentation and development of potential therapies.
authors: Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, USA.
authors: Brenda L
authors: BL
authors: Bohnsack
authors: Daniel S
authors: DS
authors: Kasprick
authors: Phillip E
authors: PE
authors: Kish
authors: Daniel
authors: D
authors: Goldman
authors: Alon
authors: A
authors: Kahana
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000869:Anterior Eye Segment / Q000002:abnormalities; D004195:Disease Models, Animal; D005123:Eye / Q000196:embryology; D005124:Eye Abnormalities / Q000235:genetics*; D015785:Eye Diseases, Hereditary; D005147:Facial Bones / Q000196:embryology; D005152:Facial Muscles / Q000196:embryology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D018398:Homeodomain Proteins / Q000235:genetics*; D017403:In Situ Hybridization; D060172:Morpholinos / Q000235:genetics; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D012886:Skull / Q000196:embryology; D014157:Transcription Factors / Q000235:genetics*; D014212:Tretinoin / Q000494:pharmacology*; D015027:Zebrafish / Q000196:embryology*; D000097577:Homeobox Protein PITX2
chemical_list: D018398:Homeodomain Proteins; D060172:Morpholinos; D012333:RNA, Messenger; D014157:Transcription Factors; D014212:Tretinoin; D000097577:Homeobox Protein PITX2