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Molecular basis for keratoconus: Lack of TrkA expression and its transcriptional repression by Sp3 (Articolo in rivista)

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Molecular basis for keratoconus: Lack of TrkA expression and its transcriptional repression by Sp3 (Articolo in rivista) (literal)

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Alessandro Lambiase*,+,?; Daniela Merlo+,§,¶,?; Cristiana Mollinari*,§; Paolo Bonini**; Anna Maria Rinaldi?; Mauro D' Amato++; Alessandra Micera*; Marco Coassin*; Paolo Rama??; Stefano Bonini*; and Enrico Garaci§§ (2005)
Molecular basis for keratoconus: Lack of TrkA expression and its transcriptional repression by Sp3
in Proceedings of the National Academy of Sciences of the United States of America
(literal)

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Alessandro Lambiase*,+,?; Daniela Merlo+,§,¶,?; Cristiana Mollinari*,§; Paolo Bonini**; Anna Maria Rinaldi?; Mauro D' Amato++; Alessandra Micera*; Marco Coassin*; Paolo Rama??; Stefano Bonini*; and Enrico Garaci§§ (literal)

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*Department of Ophthalmology, University \"Campus Bio-Medico\" and G. B. Bietti Eye Foundation, Istituto di Ricovero e Cura a Carattere Scientifico, 00155 Rome, Italy; §Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, 00161 Rome, Italy; ¶Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele, 00163 Rome, Italy; **Department of Clinical Physiopathology, University of Florence, I-50139 Florence, Italy; Departments of ?Neuroscience and §§Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, 00173 Rome, Italy; ++Microbiology and Tumor Biology Center and Strategic Research Center IRIS; Karolinska Institute, SE-171 77 Stockholm, Sweden; and ??Department of Ophthalmology, Istituto Scientifico H San Raffaele, 20132 Milan, Italy (literal)

Titolo

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

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. (literal)

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