Research article

Compound developmental eye disorders following inactivation of TGFβ signaling in neural-crest stem cells

Lars M Ittner^1,6* , Heiko Wurdak^2* , Kerstin Schwerdtfeger^1* , Thomas Kunz¹ , Fabian Ille² , Per Leveen³ , Tord A Hjalt⁴ , Ueli Suter² , Stefan Karlsson³ , Farhad Hafezi⁵ , Walter Born¹ and Lukas Sommer²

¹  Research Laboratory for Calcium Metabolism, Orthopedic University Hospital Balgrist, CH-8008 Zurich, Switzerland

²  Institute of Cell Biology, Department of Biology, ETH-Hönggerberg, CH-8093 Zurich, Switzerland

³  Departments for Molecular Medicine and Gene Therapy, Lund University, S-22184 Lund, Sweden

⁴  Department of Cell and Molecular, Biology, Section for Cell and Developmental Biology, Lund University, S-22184 Lund, Sweden

⁵  IROC, Institute for Refractive and Ophthalmic Surgery, CH-8002 Zurich, Switzerland

⁶  Current address: Brain & Mind Research Institute (BMRI), University of Sydney, NSW 2050, Australia

author email corresponding author email* Contributed equally

Journal of Biology 2005, 4:11doi:10.1186/jbiol29

Published:	14 December 2005

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 TGFβ signaling in these cells is crucial for normal eye development. In the anterior eye, TGFβ2 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. TGFβ enhances Foxc1 and induces Pitx2 expression in cell cultures. As in patients carrying mutations in PITX2 and FOXC1, TGFβ 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 TGFβ 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.

Conclusion

In the developing eye the lens acts as a TGFβ signaling center that controls the development of eye structures derived from the NC. Defective TGFβ 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 TGFβ signal modulation in ocular NC derivatives contributes to the pathophysiology of these diseases.