title: Development of extraocular muscles requires early signals from periocular neural crest and the developing eye.
abstract: OBJECTIVE
  To identify and explain morphologic changes of the extraocular muscles (EOMs) in anophthalmic patients.
  
  
  METHODS
  Retrospective medical record review of patients with congenital anophthalmia, using magnetic resonance imaging and intraoperative findings to characterize EOM morphology. We then used molecular biology techniques in zebrafish and chick embryos to determine the relationships among the developing eye, periocular neural crest, and EOMs.
  
  
  RESULTS
  In 3 human patients with bilateral congenital anophthalmia and preoperative orbital imaging, we observed a spectrum of EOM morphologies ranging from indiscernible muscle tissue to well-formed, organized EOMs. Timing of eye loss in zebrafish and chick embryos correlated with the morphology of EOM organization in the orbit (eye socket). In congenitally eyeless Rx3 zebrafish mutants, or following genetic ablation of the cranial neural crest cells, EOMs failed to organize, which was independent of other craniofacial muscle development.
  
  
  CONCLUSIONS
  Orbital development is dependent on interactions between the eye, neural crest, and developing EOMs. Timing of the ocular insult in relation to neural crest migration and EOM development is a key determinant of aberrant EOM organization. Additional research will be required to study patients with unilateral and syndromic anophthalmia and assess for possible differences in clinical outcomes of patients with varied EOM morphology.
  
  
  CONCLUSIONS
  The presence and organization of EOMs in anophthalmic eye sockets may serve as a markers for the timing of genetic or teratogenic insults, improving genetic counseling, and assisting with surgical reconstruction and family counseling efforts.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, 48105, USA.
authors.forename: Brenda L
authors.initials: BL
authors.lastname: Bohnsack
authors.forename: Donika
authors.initials: D
authors.lastname: Gallina
authors.forename: Hannah
authors.initials: H
authors.lastname: Thompson
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Kasprick
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Lucarelli
authors.forename: Gregory
authors.initials: G
authors.lastname: Dootz
authors.forename: Christine
authors.initials: C
authors.lastname: Nelson
authors.forename: Imelda M
authors.initials: IM
authors.lastname: McGonnell
authors.forename: Alon
authors.initials: A
authors.lastname: Kahana
mesh_terms: D000818:Animals; D000853:Anophthalmos / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation; D002642:Chick Embryo; D002675:Child, Preschool; D015353:Eye Enucleation; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D017403:In Situ Hybridization; D007223:Infant; D008279:Magnetic Resonance Imaging; D009024:Morphogenesis; D018995:Myosin Heavy Chains / Q000235:genetics; D009432:Neural Crest / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D009801:Oculomotor Muscles / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D009915:Orbit / Q000196:embryology* / Q000473:pathology; D018168:Receptors, Retinoic Acid / Q000235:genetics; D012189:Retrospective Studies; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000235:genetics; D000097768:Retinoic Acid Receptor gamma
chemical_list: D018398:Homeodomain Proteins; D018995:Myosin Heavy Chains; D018168:Receptors, Retinoic Acid; D029961:Zebrafish Proteins; D000097768:Retinoic Acid Receptor gamma; C488383:Rx3 protein, zebrafish; C479878:myhz2 protein, zebrafish