title: Compound developmental eye disorders following inactivation of TGFbeta signaling in neural-crest stem cells.
abstract: BACKGROUND
  Development of the eye depends partly on the periocular mesenchyme derived from the neural crest (NC), but the fate of NC cells in mammalian eye development and the signals coordinating the formation of ocular structures are poorly understood.
  
  
  RESULTS
  Here we reveal distinct NC contributions to both anterior and posterior mesenchymal eye structures and show that TGFbeta signaling in these cells is crucial for normal eye development. In the anterior eye, TGFbeta2 released from the lens is required for the expression of transcription factors Pitx2 and Foxc1 in the NC-derived cornea and in the chamber-angle structures of the eye that control intraocular pressure. TGFbeta enhances Foxc1 and induces Pitx2 expression in cell cultures. As in patients carrying mutations in PITX2 and FOXC1, TGFbeta signal inactivation in NC cells leads to ocular defects characteristic of the human disorder Axenfeld-Rieger's anomaly. In the posterior eye, NC cell-specific inactivation of TGFbeta signaling results in a condition reminiscent of the human disorder persistent hyperplastic primary vitreous. As a secondary effect, retinal patterning is also disturbed in mutant mice.
  
  
  CONCLUSIONS
  In the developing eye the lens acts as a TGFbeta signaling center that controls the development of eye structures derived from the NC. Defective TGFbeta signal transduction interferes with NC-cell differentiation and survival anterior to the lens and with normal tissue morphogenesis and patterning posterior to the lens. The similarity to developmental eye disorders in humans suggests that defective TGFbeta signal modulation in ocular NC derivatives contributes to the pathophysiology of these diseases.
authors.affiliation: Research Laboratory for Calcium Metabolism, Orthopedic University Hospital Balgrist, CH-8008 Zurich, Switzerland.|Current address: Brain & Mind Research Institute (BMRI), University of Sydney, NSW 2050, Australia.
authors.forename: Lars M
authors.initials: LM
authors.lastname: Ittner
authors.affiliation: Institute of Cell Biology, Department of Biology, ETH-Hönggerberg, CH-8093 Zurich, Switzerland.
authors.forename: Heiko
authors.initials: H
authors.lastname: Wurdak
authors.affiliation: Research Laboratory for Calcium Metabolism, Orthopedic University Hospital Balgrist, CH-8008 Zurich, Switzerland.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Schwerdtfeger
authors.affiliation: Research Laboratory for Calcium Metabolism, Orthopedic University Hospital Balgrist, CH-8008 Zurich, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kunz
authors.affiliation: Institute of Cell Biology, Department of Biology, ETH-Hönggerberg, CH-8093 Zurich, Switzerland.
authors.forename: Fabian
authors.initials: F
authors.lastname: Ille
authors.affiliation: Departments for Molecular Medicine and Gene Therapy, Lund University, S-22184 Lund, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Leveen
authors.affiliation: Department of Cell and Molecular, Biology, Section for Cell and Developmental Biology, Lund University, S-22184 Lund, Sweden.
authors.forename: Tord A
authors.initials: TA
authors.lastname: Hjalt
authors.affiliation: Institute of Cell Biology, Department of Biology, ETH-Hönggerberg, CH-8093 Zurich, Switzerland.
authors.forename: Ueli
authors.initials: U
authors.lastname: Suter
authors.affiliation: Departments for Molecular Medicine and Gene Therapy, Lund University, S-22184 Lund, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Karlsson
authors.affiliation: IROC, Institute for Refractive and Ophthalmic Surgery, CH-8002 Zurich, Switzerland.
authors.forename: Farhad
authors.initials: F
authors.lastname: Hafezi
authors.affiliation: Research Laboratory for Calcium Metabolism, Orthopedic University Hospital Balgrist, CH-8008 Zurich, Switzerland.
authors.forename: Walter
authors.initials: W
authors.lastname: Born
authors.affiliation: Institute of Cell Biology, Department of Biology, ETH-Hönggerberg, CH-8093 Zurich, Switzerland.
authors.forename: Lukas
authors.initials: L
authors.lastname: Sommer
mesh_terms: D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D005124:Eye Abnormalities / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007908:Lens, Crystalline / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009432:Neural Crest / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D014157:Transcription Factors; D016212:Transforming Growth Factor beta / Q000502:physiology*; D000097577:Homeobox Protein PITX2
chemical_list: D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000097577:Homeobox Protein PITX2; C112890:Foxc1 protein, mouse