A nonautonomous role for retinal frizzled-5 in regulating hyaloid vitreous vasculature development.
OBJECTIVE
Frizzled-5 (Fzd5) is expressed in the developing retina of multiple species and appears to play species-specific roles during eye development. The present study analyzed the effects of tissue-specific deletion of Fzd5 on mammalian eye development.


METHODS
To generate Fzd5 conditional knockout (CKO) mice, Fzd5(+/-) mice carrying the Six3-Cre transgene were crossed with Fzd5(LoxP/LoxP) mice. To determine which cell lineages in the eye had Cre recombinase activity, Six3-Cre transgenic mice were crossed with ROSA-26 reporter mice, and lacZ activity was assayed. Histologic analysis, immunofluorescence, and TUNEL labeling were performed from embryonic day (E)12.5 to postnatal stages to analyze vascularization, cell proliferation, retinal organization, and apoptosis.


RESULTS
On conditional disruption of Fzd5 specifically in the retina, but not in vitreous hyaloid vasculature (VHV), an abnormal accumulation consisting of pericytes and endothelial cells was observed in the vitreous as early as E12.5. The abundant retrolental cells persisted into postnatal stages and appeared as a pigmented intravitreal mass. In Fzd5 CKO mice there was failure of normal apoptosis of the VHV, and cells in the persistent VHV were maintained in the cell cycle up to postnatal day 23. Moreover, morphogenesis of the retina adjacent to the vasculature was disrupted, leading to retinal folds, detachment, and abnormal lamination. This phenotype is similar to that of human eye disease persistent hyperplastic primary vitreous (PHPV).


CONCLUSIONS
Selective loss of Fzd5 in the retina results in PHPV and retinal defects through an apparently cell-nonautonomous effect, revealing a potential requirement for retina-derived signals in regulating the development of the VHV.
Zhang
Jianmin
J
Department of Neurobiology and Anatomy, Moran Eye Center, University of Utah, Salt Lake City, USA.
Fuhrmann
Sabine
S
Vetter
Monica L
ML
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D051157:Frizzled Receptors / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D020868:Gene Silencing; D005838:Genotype; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D019426:Integrases / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D054514:Persistent Hyperplastic Primary Vitreous / Q000196:embryology* / Q000473:pathology; D016133:Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D012160:Retina / Q000196:embryology* / Q000473:pathology; D015792:Retinal Dysplasia / Q000196:embryology / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000473:pathology; D014822:Vitreous Body / Q000098:blood supply*
D051157:Frizzled Receptors; C403211:Fzd5 protein, mouse; D043562:Receptors, G-Protein-Coupled; C045073:Cre recombinase; D019426:Integrases
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