Retinoic acid receptor-dependent survival of olfactory sensory neurons in postnatal and adult mice.
To address the hypothesis that retinoids produced by synthesizing enzymes present in the primary olfactory system influence the mouse olfactory sensory map, we expressed a dominant-negative retinoic acid receptor selectively in olfactory sensory neurons. We show that neurons deficient in nuclear retinoid signaling are responsive to odors and form correct odorant receptor-specific axonal projections to target neurons in the olfactory bulb of the brain. Subsequent to the formation of the map, the neurons die prematurely by retrograde-driven caspase-3 activation, which resembles the previously described mechanism of neural death after olfactory bulb ablation. This neurodegenerative event is initiated the second postnatal week and occurs in the adult animal without a compensatory increase of progenitor cell proliferation. In addition, we find that nuclear retinoid signaling is required for the expression of a retinoic acid-degrading enzyme, Cyp26B1, in a small fraction of mature neurons. Collectively, the results provide evidence for a role of locally regulated retinoid metabolism in neuroprotection and in determining population size of neurons at a late stage of neural circuit formation.
Department of Molecular Biology, Umeå University, SE901 87 Umeå, Sweden.
Maria
M
Hägglund
Anna
A
Berghard
Jörg
J
Strotmann
Staffan
S
Bohm
D000375:Aging / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D020439:Growth Cones / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009830:Olfactory Bulb / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D009831:Olfactory Mucosa / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D009832:Olfactory Nerve / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D009833:Olfactory Pathways / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D018034:Olfactory Receptor Neurons / Q000166:cytology / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D000072516:Retinoic Acid 4-Hydroxylase; D012183:Retrograde Degeneration / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology; D012903:Smell / Q000235:genetics; D014212:Tretinoin / Q000378:metabolism
D018168:Receptors, Retinoic Acid; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases