ßA3/A1-crystallin and persistent fetal vasculature (PFV) disease of the eye.

BACKGROUND: Persistent fetal vasculature (PFV) is a human disease in which the fetal vasculature of the eye fails to regress normally. The fetal, or hyaloid, vasculature nourishes the lens and retina during ocular development, subsequently regressing after formation of the retinal vessels. PFV causes serious congenital pathologies and is responsible for as much as 5% of blindness in the United States. SCOPE OF REVIEW: The causes of PFV are poorly understood, however there are a number of animal models in which aspects of the disease are present. One such model results from mutation or elimination of the gene (Cryba1) encoding ßA3/A1-crystallin. In this review we focus on the possible mechanisms whereby loss of functional ßA3/A1-crystallin might lead to PFV. MAJOR CONCLUSIONS: Cryba1 is abundantly expressed in the lens, but is also expressed in certain other ocular cells, including astrocytes. In animal models lacking ßA3/A1-crystallin, astrocyte numbers are increased and they migrate abnormally from the retina to ensheath the persistent hyaloid artery. Evidence is presented that the absence of functional ßA3/A1-crystallin causes failure of the normal acidification of endolysosomal compartments in the astrocytes, leading to impairment of certain critical signaling pathways, including mTOR and Notch/STAT3. GENERAL SIGNIFICANCE: The findings suggest that impaired endolysosomal signaling in ocular astrocytes can cause PFV disease, by adversely affecting the vascular remodeling processes essential to ocular development, including regression of the fetal vasculature. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease.

Prenatal ultrasonographic detection of ophthalmic diseases.

Four patients with prenatal sonographic findings suggestive of ophthalmic pathology were detected in utero. The definitive diagnoses of infantile fibrosarcoma, persistent hyperplastic primary vitreous/persistent fetal vasculature, Fraser syndrome, and microphthalmia with coloboma and retrobulbar cyst were made postnatally. High-resolution intrauterine sonograms expedited ophthalmic referral and influenced prenatal planning.

A nonautonomous role for retinal frizzled-5 in regulating hyaloid vitreous vasculature development.

PURPOSE: 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.

Retinopathy of prematurity: clinic and pathogenesis. Disproportion between apoptosis of vitreal and proliferation of retinal vascularization.

The structure of adult human vitreous condensations (tractus, membranelles) corresponds to the structure of obliterated embryonal vasa hyaloidea. Some embryonal hyaloidal vessels and structures extend from the tunica vasculosa lentis and attach to the retina between the equator and ora serrata. In normal fetal development, these hyaloidal vessels and structures successively disappear because of apoptosis. The lower the birth weight of a premature infant, the higher the risk of retinopathy of prematurity (ROP) due to the disproportion between the regression of vasa hyaloidea (hyaloideoretinal adherences) and the proliferation of retinal vessels. This may be caused by an enhanced growth of retinal vessels (or a delayed regression of vasa hyaloidea). The growth of retinal vessels stops at a barrier formed by the retina-attaching hyaloidal remnants (vessels), resulting in a demarcation line and ROP. The same retinal vessels may then, as a fibrovascular tissue, overgrow the remnants of retina-attaching hyaloidal structures (as guiding formations) through the vitreous cavity up to the tunica vasculosa lentis. The process may result in the progression from ROP stage 2 to ROP stage 5.