Cited2 is required for the proper formation of the hyaloid vasculature and for lens morphogenesis.
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-1alpha) 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.
Chen
Yu
Y
Department of Biochemistry and Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Doughman
Yong-qiu
YQ
Gu
Shi
S
Jarrell
Andrew
A
Aota
Shin-ichi
S
Cvekl
Ales
A
Watanabe
Michiko
M
Dunwoodie
Sally L
SL
Johnson
Randall S
RS
van Heyningen
Veronica
V
Kleinjan
Dirk A
DA
Beebe
David C
DC
Yang
Yu-Chung
YC
D000818:Animals; D016923:Cell Death; D049109:Cell Proliferation; D003315:Cornea / Q000002:abnormalities; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D019426:Integrases; D007908:Lens, Crystalline / Q000098:blood supply* / Q000196:embryology* / Q000473:pathology; D051379:Mice; D009024:Morphogenesis; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000172:deficiency / Q000378:metabolism*; D014822:Vitreous Body / Q000002:abnormalities / Q000098:blood supply
C110087:Cited2 protein, mouse; D005136:Eye Proteins; D018398:Homeodomain Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins; D015534:Trans-Activators; C045073:Cre recombinase; D019426:Integrases