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First published online 24 July 2008
doi: 10.1242/dev.021097

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Cited2 is required for the proper formation of the hyaloid vasculature and for lens morphogenesis

¹ Department of Biochemistry and Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
² Department of Pediatrics, Rainbow Babies' and Children's Hospital, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
³ Developmental Biology, Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan.
⁴ Departments of Ophthalmology and Visual Sciences and Molecular Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
⁵ Developmental Biology Program, The Victor Chang Cardiac Research Institute, 384 Victoria Street, Darlinghurst, NSW 2010, Australia.
⁶ Molecular Biology Section, Division of Biological Sciences, School of Medicine, UCSD, La Jolla, CA 92093, USA.
⁷ MRC Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, UK.
⁸ Department of Ophthalmology and Visual Sciences, Department of Cell Biology and Physiology, Washington University, St Louis, MO 63110, USA.

^* Author for correspondence (e-mail: yu-chung.yang{at}case.edu)

Accepted 1 July 2008

Cited2 is a transcriptional modulator with pivotal roles in different biological processes. Cited2-deficient mouse embryos manifested two major defects in the developing eye. An abnormal corneal-lenticular stalk was characteristic of Cited2^-/- developing eyes, a feature reminiscent of Peters' anomaly, which can be rescued by increased Pax6 gene dosage in Cited2^-/- embryonic eyes. In addition, the hyaloid vascular system showed hyaloid hypercellularity consisting of aberrant vasculature, which might be correlated with increased VEGF expression in the lens. Deletion of Hif1a (which encodes HIF-1) in Cited2^-/- lens specifically eliminated the excessive accumulation of cellular mass and aberrant vasculature in the developing vitreous without affecting the corneal-lenticular stalk phenotype. These in vivo data demonstrate for the first time dual functions for Cited2: one upstream of, or together with, Pax6 in lens morphogenesis; and another in the normal formation of the hyaloid vasculature through its negative modulation of HIF-1 signaling. Taken together, our study provides novel mechanistic revelation for lens morphogenesis and hyaloid vasculature formation and hence might offer new insights into the etiology of Peters' anomaly and ocular hypervascularity.

Key words: Cited2, Hyaloid vasculature, Lens development, Mouse

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