TY - JOUR
T1 - Manipulations of ACHE gene expression suggest non-catalytic involvement of acetylcholinesterase in the functioning of mammalian photoreceptors but not in retinal degeneration
AU - Broide, Ron S.
AU - Grifman, Mirta
AU - Loewenstein, Anat
AU - Grisaru, Dan
AU - Timberg, Rina
AU - Stone, Jonathan
AU - Shani, Moshe
AU - Patrick, James W.
AU - Soreq, Hermona
PY - 1999/8/25
Y1 - 1999/8/25
N2 - 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-Fos overproduction. In human embryos (20 weeks), most retinal neurons express AChEmRNA. Surprisingly, only the continually remodeling photoreceptors express AChEmRNA in aged humans (> 70 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.
AB - 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-Fos overproduction. In human embryos (20 weeks), most retinal neurons express AChEmRNA. Surprisingly, only the continually remodeling photoreceptors express AChEmRNA in aged humans (> 70 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.
KW - Cholinesterase inhibitor
KW - Gene, fos
KW - In situ hybridization
KW - Mice, transgenic
KW - Photoreceptor, vertebrate
UR - http://www.scopus.com/inward/record.url?scp=0032693784&partnerID=8YFLogxK
U2 - 10.1016/S0169-328X(99)00169-2
DO - 10.1016/S0169-328X(99)00169-2
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C2 - 10521568
AN - SCOPUS:0032693784
SN - 0169-328X
VL - 71
SP - 137
EP - 148
JO - Molecular Brain Research
JF - Molecular Brain Research
IS - 2
ER -