Manipulations of ACHE gene expression suggest non-catalytic involvement ofacetylcholinesterase in the functioning of mammalian photoreceptors but not in retinal degeneration

To explore role(s) of acetylcholinesterase (AChE) in functioning and diseas ed photoreceptors, we studied normal (rd/+) and degenerating (rd/rd) murine retinas. All retinal neurons, expressed AChEmRNA throughout fetal developm ent. AChE and c-Fos mRNAs peaked at post-natal days 10-12, when apoptosis o f rd/rd photoreceptors begins, Moreover, c-Fos and AChEmRNA were co-overexp ressed in rd/rd mice producing transgenic human (h), and host (m) AChE, but not in rd/+ mice. However, mAChE overexpression also occurred in transgeni cs expressing human serum albumin. Drastic variations in AChE catalytic act ivity were ineffective during development. Neither transgenic excess nor di isopropylfluorophosphonate (DFP) inhibition (80%) affected the rd phenotype ; nor did DFP exposure induce photoreceptor degeneration or affect other ke y cholinergic proteins in rd/+ mice, unlike reports of adult mice and despi te massive induction under DFP of c-Fos overproduction. In human embryos (2 0 weeks), most retinal neurons express AChEmRNA. Surprisingly, only the con tinually remodeling photoreceptors express AChEmRNA in aged humans (> 70 ye ars). Therefore, the extreme retinal sensitivity to AChE modulation may ref lect non-catalytic function(s) of AChE in adult photoreceptors. These findi ngs exclude AChE as causing the rd phenotype, suggest that its primary func tion(s) in mammalian retinal development are non-catalytic ones and indicat e special role(s) for the AChE protein in adult photoreceptors, (C) 1999 El sevier Science B.V. All rights reserved.