Altered expression of metallothionein-I and -II and their receptor megalin in inherited photoreceptor degeneration.
OBJECTIVE
To examine in rodent models of retinitis pigmentosa (RP) the expression of the neuroprotectants metallothionein-I and -II and of megalin, an endocytic receptor that mediates their transport into neurons.


METHODS
Gene and protein expression were analyzed in retinas of rd1 and rds mice and in those of RCS (Royal College of Surgeons) rats of various ages. Glial cell markers (cellular retinaldehyde binding protein, CRALBP; glial fibrillary acidic protein, GFAP; CD11b; and isolectin B4) were used to establish the identity of the cells.


RESULTS
Metallothionein-I and -II gene expression increased with age in normal and degenerating retinas and was significantly greater in the latter. Protein expression, corresponding to metallothionein-I+II, was first observed in rd1 mice in Müller cells at postnatal day (P)12 and in rds mice at P16, coinciding with the onset of GFAP expression in these cells. In RCS rats, the same distribution was observed, but not until P32, long after the onset of GFAP expression. Metallothionein-I+II was observed also in a small number of microglial cells. Megalin was expressed in the nerve fiber layer and in the region of the inner and outer segments in normal animals, but expression in the outer retina was lost with age in degenerating retinas.


CONCLUSIONS
Induction of metallothionein-I and -II occurs in the RP models studied and correlates with glial activation. The progressive loss of megalin suggests that transport of metallothionein-I+II into the degenerating photoreceptors (from e.g., Müller cells), could be impaired, potentially limiting the actions of these metallothioneins.
Wunderlich
Kirsten A
KA
Department of Ophthalmology, Clinical Sciences Lund, Lund University, Lund, Sweden.
Leveillard
Thierry
T
Penkowa
Milena
M
Zrenner
Eberhart
E
Perez
Maria-Thereza
MT
D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001360:Avidin / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000235:genetics; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein; D020287:In Situ Nick-End Labeling; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000378:metabolism*; D008668:Metallothionein / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000378:metabolism / Q000473:pathology
D015415:Biomarkers; D005904:Glial Fibrillary Acidic Protein; D026561:Low Density Lipoprotein Receptor-Related Protein-2; C491055:Mt2A protein, rat; D009419:Nerve Tissue Proteins; C528900:glial fibrillary astrocytic protein, mouse; D001360:Avidin; D008668:Metallothionein; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C517438:Pde6b protein, mouse