Molecular basis for keratoconus: Lack of TrkA expression and its transcriptional repression by Sp3

Abstract

Keratoconus is the most common corneal dystrophy that leads to severe visual impairment. Although the major etiological factors are genetic, the pathogenetic mechanism(s) is unknown. No medical treatments exist, and the only therapeutic approach is corneal transplantation. Recent data demonstrate the involvement of nerve growth factor (NGF) in trophism and corneal wound healing. In this study, we investigated alterations in the NGF pathway in keratoconus-affected corneas and found a total absence of the NGF-receptor TrkA (TrkA NGFR ) expression and a decreased expression of NGF and p75 NTR . The absence of TrkA NGFR expression was associated with a strong increase in the Sp3 repressor short isoform(s) and a lack of the Sp3 activator long isoform. Sp3 is a bifunctional transcription factor that has been reported to stimulate or repress the transcription of numerous genes. Indeed, we found that Sp3 short isoform(s) overexpression in cell culture results in a down-regulation of TrkA NGFR expression. We suggest that an imbalance in Sp transcription-factor isoforms may play a role in controlling the NGF signaling, thus contributing to the pathogenesis of keratoconus. This mechanism for the transcriptional repression of the TrkA NGFR gene can provide the platform for the development of a therapeutic strategy.cornea ͉ nerve growth factor ͉ transcription factor ͉ corneal dystrophy ͉ nerve growth factor's receptors

Sp3‐Mediated VEGF regulation is dependent on phosphorylation by extra‐cellular signals regulated kinases (Erk)

“…Our data further increase the complexity of the regulation of Sp3 in particular the fact that different Sp3 isoforms result for internal initiation of translation (Kennett et al, 1997) but also the recent advances showing that sumoylation of Sp3 represses its transcriptional activity (Sapetschnig et al, 2002(Sapetschnig et al, , 2004Spengler et al, 2005). It is interesting to note that the Erk phosphorylation site is situated in the long Sp3 isoform, which behaves as an activator of transcription (Kennett et al, 1997) or a repressor depending on the promoter (Lambiase et al, 2005). Sp3 was also demonstrated to be a tyrosine phosphorylated protein and increased phosphorylation was already observed in Ha-Ras transformed cells (Bakovic et al, 2003).…”

Association between Mediators in the Tear Fluid and the Severity of Keratoconus

“…NGF is known to promote corneal nerve trophism and wound healing, and its role after refractive procedures, neurodegenerative corneal ulcers and dry eye has already been investigated [18,24,25]. The impairment of corneal innervation has been suggested to play a role in the pathogenesis of KC, and a significant reduction in NGF expression has been detected in KC corneas as part of an imbalance in the NGF signaling pathway [8,26]. Reduced numbers of stromal nerve fiber bundles together with an increase in tortuosity and nerve fiber diameter can explain the presence of prominent corneal nerves in KC [27].…”

“…Factors determining or affecting the progression or stabilization of KC have not been well understood [3,4]. During tissue degradation - a hallmark of the disease - the expression of inflammatory mediators such as proinflammatory cytokines, cell adhesion molecules and matrix metalloproteinases (MMPs), as well as other enzymes and growth factors, has also been described [4,5,6,7,8,9,10,11,12,13]. Recent studies have suggested a role of the inflammatory events in the pathogenesis of KC [4,14].…”

Conditional Deletion of the Mouse Klf4 Gene Results in Corneal Epithelial Fragility, Stromal Edema, and Loss of Conjunctival Goblet Cells

“…Relatively little is known about the genetic network of transcription factors required for embryonic morphogenesis, postnatal maturation, and maintenance of cornea (1,2,10,12,20,23,26,32,39,46,47,55,59,60,65). Serial analysis of gene expression identified KLF4, a member of the Krüppel-like transcription factor (KLF) subfamily of Cys2-His2 zinc finger proteins, as one of the most highly expressed transcription factors in both 9-day-old and 6-week-old mouse cornea (50).…”