Role of INK4a locus in normal eye development and cataract genesis

Department of Molecular and Cell Biology, Sungkyunkwan University, Sŏul, Seoul, South Korea
Mechanisms of Ageing and Development (Impact Factor: 3.4). 08/2006; 127(7):633-8. DOI: 10.1016/j.mad.2006.02.010
Source: PubMed


The murine INK4a locus encodes the critical tumor suppressor proteins, p16(INK4a) and p19(ARF). Mice lacking both p16(INK4a) and p19(ARF) (INK4a-/-) in their FVB/NJ genetic backgrounds developed cataracts and microophthalmia. Histopathologically, INK4a-/- mice showed defects in the developmental regression of the hyaloid vascular system (HVS), retinal dysplasia, and cataracts with numerous vacuolations, closely resembling human persistent hyperplastic primary vitreous (PHPV). Ocular defects, such as retinal fold and abnormal migration of lens fiber cells, were observed as early as embryonic day (E) 15.5, thereby resulting in the abnormal differentiation of the lens. We also found that ectopic expression of p16(INK4a) resulted in the induction of gammaF-crystallin, suggesting an important role of INK4a locus during mouse eye development, and also providing insights into the potential genetic basis of human cataract genesis.

Download full-text


Available from: Cheolho Cheong, Dec 18, 2013
  • Source
    • "Haematoxylin and eosin (H&E) staining and immunohistochemistry Kidneys were fixed in 10% formalin (Sigma, St. Louis, MO, USA), embedded in paraffin and sectioned at 4-lm intervals. For histological examination, the sections were stained with H&E as described previously (Cheong et al. 2006). To perform the immunohistochemical study, the paraffin sections were incubated with 0.3% H 2 O 2 for 30 min to eliminate endogenous peroxidases, followed by several PBS rinses. "
    [Show abstract] [Hide abstract]
    ABSTRACT: p23 is a cochaperone of heat shock protein 90 and also interacts functionally with numerous steroid receptors and kinases. However, the in vivo roles of p23 remain unclear. To explore its in vivo function, we generated the transgenic (TG) mice ubiquitously overexpressing p23. The p23 TG mice spontaneously developed kidney abnormalities closely resembling human hydronephrosis. Consistently, kidney functions deteriorate significantly in the p23 TG mice compared to their wild-type (WT) littermates. Furthermore, the expression of target genes for aryl hydrocarbon receptor (AhR), such as cytochrome P450, family 1, subfamily A, polypeptide 1 (Cyp1A1) and cytochrome P450, family 1, subfamily B, polypeptide 1 (Cyp1B1), were induced in the kidneys of the p23 TG mice. These results indicate that the overexpression of p23 contributes to the development of hydronephrosis through the upregulation of the AhR pathway in vivo.
    Preview · Article · Feb 2011 · International Journal of Experimental Pathology
  • Source
    • "with retinal dysplasia and defects in the regression of the embryonic hyaloid vascular system. The first alterations in the lens occur at embryonic day 15.5 as altered migration of lens fibre cells resulting in disturbed differentiation of the lens (Cheong et al. 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Much of our knowledge about the function of genes in cataracts has been derived from the molecular analysis of spontaneous or induced mutations in the mouse. Mutations affecting the mouse lens can be identified easily by visual inspection, and a remarkable number of mutant lines have been characterized. In contrast to humans, most of the genetic mouse cataract models suffer from congenital cataracts, and only a few develop cataracts in old age. Therefore, the mouse cataract models contributed rather to the understanding of lens development than to the ageing process taking place in the lens. A prerequisite for molecular analysis is the chromosomal localization of the gene. In this review, several mouse models will be discussed with emphasis on the underlying genetic basis rather than the morphological features as exemplified by the following: (i) the most frequent mutations in congenital cataracts affect genes coding for gamma-crystallins (gene symbol: Cryg); (ii) some postnatal, progressive cataracts have been characterized by mutations in the beta-crystallin encoding genes (Cryb); (iii) mutations in genes coding for membrane proteins like MIP or connexins lead to congenital cataracts; (iv) mutations in genes coding for transcription factors such as FoxE3, Maf, Sox1, and Six5 cause cataracts; (v) mouse models suffering from hereditary age-related cataracts (e.g. Emory cataract) have not yet been characterized genetically. In conclusion, a broad variety of hereditary congenital cataracts are well understood at the molecular level. Further, expression patterns of the affected genes in several other tissues and organs outside the eye, is making it increasingly clear that isolated cataracts are the exception rather than the rule. By further understanding the pleiotropic effects of these genes, we might recognize cataracts as an easily visible biomarker for a number of systemic syndromes.
    Preview · Article · Dec 2009 · Journal of Genetics
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We describe a proteomic approach to investigate the differential protein expression patterns and identify the physiologically relevant angiogenic and antiangiogenic factors involved in the hyaloid vascular system regression. Differentially expressed proteins were identified using two-dimensional gel electrophoresis followed by nanoflow chromatography coupled with tandem mass spectrometry. These proteins are expected to provide insight as to their function in the early maintenance and eventual regression of the hyaloid vascular system.
    Full-text · Article · Nov 2008 · Journal of Proteome Research
Show more