INVESTIGADORES
SIMON Maria Victoria
congresos y reuniones científicas
Título:
Activation Of The p38 MAP/kinase Pathway Is Required For Retinoic Acid Effects On Retina Photoreceptors
Autor/es:
POLITI L. E..; DE GENARO P. A.; SIMÓN M.V.; ROTSTEIN N. P.
Reunión:
Congreso; ARVO 2012 Annual Meeting; 2012
Institución organizadora:
ARVO
Resumen:
Purpose: Retinoic acid (RA) has a pivotal role in promoting cell
differentiation in several tissues. This vitamin A metabolite is critical
during the development of the nervous system, including the retina. In
addition, RA has been shown to induce apoptosis in diverse cell types.
However, the mechanisms by which RA induces these seemingly
contradictory effects remain elusive. We here investigated these effects of
RA in rat retina neurons.Retinoic acid (RA) has a pivotal role in promoting cell
differentiation in several tissues. This vitamin A metabolite is critical
during the development of the nervous system, including the retina. In
addition, RA has been shown to induce apoptosis in diverse cell types.
However, the mechanisms by which RA induces these seemingly
contradictory effects remain elusive. We here investigated these effects of
RA in rat retina neurons.
Methods: Pure neuronal cultures prepared from rat retinas were grown in
chemically defined media and supplemented at day 0 with RA, with or
without docosahexaenoic acid (DHA), a survival lipid molecule for
photoreceptors (PHRs). To evaluate p38 involvement in RA effects,
phosphorylated-p38 levels were determined; cultures were also treated
with or without SB203580, a p38 specific inhibitor, before RA addition.
Several parameters of differentiation and apoptosis were evaluated at
different times in vitro. The effect of the pan caspase inhibitor
Z-VAD-FMK on apoptosis was also determined.Pure neuronal cultures prepared from rat retinas were grown in
chemically defined media and supplemented at day 0 with RA, with or
without docosahexaenoic acid (DHA), a survival lipid molecule for
photoreceptors (PHRs). To evaluate p38 involvement in RA effects,
phosphorylated-p38 levels were determined; cultures were also treated
with or without SB203580, a p38 specific inhibitor, before RA addition.
Several parameters of differentiation and apoptosis were evaluated at
different times in vitro. The effect of the pan caspase inhibitor
Z-VAD-FMK on apoptosis was also determined.
Results: RA significantly increased opsin and peripherin expression in
PHRs and stimulated axon outgrowth in PHRs and amacrine cells. RA
selectively increased apoptosis of PHRs by day 3 in vitro, which was
prevented by pre-treatment with the caspase pan-inhibitor Z-VAD-FMK.
RA effects on opsin expression and apoptosis were mediated by activation
of the p38-MAPK pathway; RA promoted p38 phosphorylation, whereas
SB203580 blocked these effects, without affecting axon outgrowth.
Noteworthy, RA early induction of apoptosis was prevented by
supplementing the cultures with DHA.
selectively increased apoptosis of PHRs by day 3 in vitro, which was
prevented by pre-treatment with the caspase pan-inhibitor Z-VAD-FMK.
RA effects on opsin expression and apoptosis were mediated by activation
of the p38-MAPK pathway; RA promoted p38 phosphorylation, whereas
SB203580 blocked these effects, without affecting axon outgrowth.
Noteworthy, RA early induction of apoptosis was prevented by
supplementing the cultures with DHA.
Conclusions: This work shows that RA promoted differentiation in PHR
while simultaneously inducing an early onset of apoptosis. Both effects
were mediated by activation of the p38-MAPK pathway, whereas RA
stimulation of axon outgrowth was not, implying that RA simultaneously
activated different signaling pathways in retinal neurons. DHA prevention
of RA-induced apoptosis suggests that RA might activate apoptosis in
PHRs with a deficient supply of trophic factors, underscoring the need of
an exquisite coordination in the supply of these factors. Thus, the dual
effects of RA might help to establish the final number of photoreceptors
during retina development.This work shows that RA promoted differentiation in PHR
while simultaneously inducing an early onset of apoptosis. Both effects
were mediated by activation of the p38-MAPK pathway, whereas RA
stimulation of axon outgrowth was not, implying that RA simultaneously
activated different signaling pathways in retinal neurons. DHA prevention
of RA-induced apoptosis suggests that RA might activate apoptosis in
PHRs with a deficient supply of trophic factors, underscoring the need of
an exquisite coordination in the supply of these factors. Thus, the dual
effects of RA might help to establish the final number of photoreceptors
during retina development.RA significantly increased opsin and peripherin expression in
PHRs and stimulated axon outgrowth in PHRs and amacrine cells. RA
selectively increased apoptosis of PHRs by day 3 in vitro, which was
prevented by pre-treatment with the caspase pan-inhibitor Z-VAD-FMK.
RA effects on opsin expression and apoptosis were mediated by activation
of the p38-MAPK pathway; RA promoted p38 phosphorylation, whereas
SB203580 blocked these effects, without affecting axon outgrowth.
Noteworthy, RA early induction of apoptosis was prevented by
supplementing the cultures with DHA.
selectively increased apoptosis of PHRs by day 3 in vitro, which was
prevented by pre-treatment with the caspase pan-inhibitor Z-VAD-FMK.
RA effects on opsin expression and apoptosis were mediated by activation
of the p38-MAPK pathway; RA promoted p38 phosphorylation, whereas
SB203580 blocked these effects, without affecting axon outgrowth.
Noteworthy, RA early induction of apoptosis was prevented by
supplementing the cultures with DHA.
Conclusions: This work shows that RA promoted differentiation in PHR
while simultaneously inducing an early onset of apoptosis. Both effects
were mediated by activation of the p38-MAPK pathway, whereas RA
stimulation of axon outgrowth was not, implying that RA simultaneously
activated different signaling pathways in retinal neurons. DHA prevention
of RA-induced apoptosis suggests that RA might activate apoptosis in
PHRs with a deficient supply of trophic factors, underscoring the need of
an exquisite coordination in the supply of these factors. Thus, the dual
effects of RA might help to establish the final number of photoreceptors
during retina development.This work shows that RA promoted differentiation in PHR
while simultaneously inducing an early onset of apoptosis. Both effects
were mediated by activation of the p38-MAPK pathway, whereas RA
stimulation of axon outgrowth was not, implying that RA simultaneously
activated different signaling pathways in retinal neurons. DHA prevention
of RA-induced apoptosis suggests that RA might activate apoptosis in
PHRs with a deficient supply of trophic factors, underscoring the need of
an exquisite coordination in the supply of these factors. Thus, the dual
effects of RA might help to establish the final number of photoreceptors
during retina development.