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

Alessandro Lambiase, Daniela Merlo, Cristiana Mollinari, Paolo Bonini, Anna Maria Rinaldi, Mauro D'Amato, Alessandra Micera, Marco Coassin, Paolo Rama, Stefano Bonini, Enrico Garaci

Research output: Contribution to journalArticle

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 (TrkANGFR) expression and a decreased expression of NGF and p75 NTR. The absence of TrkANGFR 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 TrkANGFR 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 TrkANGFR gene can provide the platform for the development of a therapeutic strategy.

Original languageEnglish
Pages (from-to)16795-16800
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number46
DOIs
Publication statusPublished - Nov 15 2005

Keywords

  • Cornea
  • Corneal dystrophy
  • Nerve growth factor
  • Nerve growth factor's receptors
  • Transcription factor

ASJC Scopus subject areas

  • Genetics
  • General

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