Manipulations of ACHE gene expression suggest non-catalytic involvement of acetylcholinesterase in the functioning of mammalian photoreceptors but not in retinal degeneration.
To explore role(s) of acetylcholinesterase (AChE) in functioning and diseased photoreceptors, we studied normal (rd/+) and degenerating (rd/rd) murine retinas. All retinal neurons, expressed AChEmRNA throughout fetal development. AChE and c-Fos mRNAs peaked at post-natal days 10-12, when apoptosis of rd/rd photoreceptors begins. Moreover, c-Fos and AChEmRNA were co-overexpressed in rd/rd mice producing transgenic human (h), and host (m) AChE, but not in rd/+ mice. However, mAChE overexpression also occurred in transgenics expressing human serum albumin. Drastic variations in AChE catalytic activity were ineffective during development. Neither transgenic excess nor diisopropylfluorophosphonate (DFP) inhibition (80%) affected the rd phenotype; nor did DFP exposure induce photoreceptor degeneration or affect other key cholinergic proteins in rd/+ mice, unlike reports of adult mice and despite massive induction under DFP of c-Fos70 years). Therefore, the extreme retinal sensitivity to AChE modulation may reflect non-catalytic function(s) of AChE in adult photoreceptors. These findings exclude AChE as causing the rd phenotype, suggest that its primary function(s) in mammalian retinal development are non-catalytic ones and indicate special role(s) for the AChE protein in adult photoreceptors.
Broide
R S
RS
Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
Grifman
M
M
Loewenstein
A
A
Grisaru
D
D
Timberg
R
R
Stone
J
J
Shani
M
M
Patrick
J W
JW
Soreq
H
H
D000110:Acetylcholinesterase / Q000235:genetics*; D000328:Adult; D000375:Aging / Q000235:genetics; D000818:Animals; D002384:Catalysis; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004253:DNA Nucleotidylexotransferase / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D020419:Photoreceptor Cells, Vertebrate / Q000502:physiology*; D012162:Retinal Degeneration / Q000201:enzymology*
D002800:Cholinesterase Inhibitors; D004253:DNA Nucleotidylexotransferase; D000110:Acetylcholinesterase