title: Microphthalmia resulting from MSX2-induced apoptosis in the optic vesicle.
abstract: OBJECTIVE
  Microphthalmia is a relatively common ocular malformation. Molecular mechanisms that lead to this dire condition are largely unknown. Msx genes have been shown to be expressed in the developing eye. In the Msx1;Msx2, double mutant mouse, eye development arrests early in embryogenesis. To investigate possible functions of Msx2 in early ocular development, we created transgenic animals that overexpress Msx2.
  
  
  METHODS
  Msx2 transgenic embryos and nontransgenic littermates were examined histopathologically. The effect of Msx2 overexpression on retinal cell proliferation was assayed by bromodeoxyuridine (BrdU) incorporation and immunohistochemical staining. Apoptosis was determined by TUNEL labeling. Expression of retina and retinal pigmented epithelium (RPE)-specific genes was investigated by performing in situ hybridization or immunohistochemical staining.
  
  
  RESULTS
  Forced expression of the Msx2 gene resulted in optic nerve aplasia and microphthalmia in all transgenic animals. In developing retinas of Msx2 transgenic animals, proliferation was significantly reduced and increased numbers of retinal cells underwent apoptosis. Marker analysis showed suppression of Bmp4 and induction of Bmp7 gene expression in the optic vesicle. Ectopic concurrent expression of the RPE cell markers Cx43 and Trp-2 in the neural retinal layer suggests cell fate respecification.
  
  
  CONCLUSIONS
  These results indicate that forced expression of Msx2 perturbs BMP signaling in the developing eye and is accompanied by an increase in retinal cell death and a reduction in cell proliferation. Thus, deregulated Msx2 gene expression may be a plausible genetic mechanism by which the autosomal dominant form of congenital microphthalmia may arise.
authors.affiliation: Center for Craniofacial Molecular Biology, Division of Craniofacial Sciences and Therapeutics, School of Dentistry, Los Angeles, California 90033, USA.
authors.forename: Lan-Ying
authors.initials: LY
authors.lastname: Wu
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: David R
authors.initials: DR
authors.lastname: Hinton
authors.forename: Lin
authors.initials: L
authors.lastname: Guo
authors.forename: Shaoyun
authors.initials: S
authors.lastname: Jiang
authors.forename: Jian Tao
authors.initials: JT
authors.lastname: Wang
authors.forename: Angie
authors.initials: A
authors.lastname: Zeng
authors.forename: Jian Bao
authors.initials: JB
authors.lastname: Xie
authors.forename: Malcolm
authors.initials: M
authors.lastname: Snead
authors.forename: Charles
authors.initials: C
authors.lastname: Shuler
authors.forename: Robert E
authors.initials: RE
authors.lastname: Maxson
authors.forename: Yi-Hsin
authors.initials: YH
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D055415:Bone Morphogenetic Protein 4; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000235:genetics; D001973:Bromodeoxyuridine / Q000378:metabolism; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D018398:Homeodomain Proteins / Q000235:genetics*; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D008850:Microphthalmos / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009900:Optic Nerve / Q000002:abnormalities* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D012160:Retina / Q000196:embryology / Q000378:metabolism / Q000473:pathology*; D016212:Transforming Growth Factor beta
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C084119:MSX2 protein; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D001973:Bromodeoxyuridine