Molecular basis for keratoconus: lack of TrkA expression and its transcriptional repression by Sp3.
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.
Lambiase
Alessandro
A
Department of Ophthalmology, University Campus Bio-Medico, G. B. Bietti Eye Foundation, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy. a.lambiase@unicampus.it
Merlo
Daniela
D
Mollinari
Cristiana
C
Bonini
Paolo
P
Rinaldi
Anna Maria
AM
D' Amato
Mauro
M
Micera
Alessandra
A
Coassin
Marco
M
Rama
Paolo
P
Bonini
Stefano
S
Garaci
Enrico
E
D001483:Base Sequence; D002478:Cells, Cultured; D003315:Cornea / Q000378:metabolism / Q000473:pathology; D017931:DNA Primers; D015536:Down-Regulation; D017930:Genes, Reporter; D006801:Humans; D007640:Keratoconus / Q000235:genetics*; D008856:Microscopy, Fluorescence; D020932:Nerve Growth Factor / Q000502:physiology; D020917:Receptor, trkA / Q000235:genetics*; D051705:Sp3 Transcription Factor / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*
D017931:DNA Primers; D051705:Sp3 Transcription Factor; D020932:Nerve Growth Factor; D020917:Receptor, trkA