Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Aging / physiology
-
Animals
-
Animals, Newborn
-
Apoptosis / genetics*
-
Caspase 3
-
Caspases / metabolism
-
Cell Differentiation / physiology
-
Cell Survival / physiology
-
Cytochrome P-450 Enzyme System / metabolism
-
Female
-
Growth Cones / metabolism
-
Growth Cones / ultrastructure
-
Male
-
Mice
-
Mice, Inbred C57BL
-
Mice, Transgenic
-
Olfactory Bulb / cytology
-
Olfactory Bulb / growth & development*
-
Olfactory Bulb / metabolism
-
Olfactory Mucosa / cytology
-
Olfactory Mucosa / growth & development*
-
Olfactory Mucosa / metabolism
-
Olfactory Nerve / cytology
-
Olfactory Nerve / growth & development
-
Olfactory Nerve / metabolism
-
Olfactory Pathways / cytology
-
Olfactory Pathways / growth & development*
-
Olfactory Pathways / metabolism
-
Olfactory Receptor Neurons / cytology
-
Olfactory Receptor Neurons / metabolism*
-
Receptors, Retinoic Acid / genetics*
-
Retinoic Acid 4-Hydroxylase
-
Retrograde Degeneration / genetics
-
Retrograde Degeneration / metabolism
-
Retrograde Degeneration / physiopathology
-
Signal Transduction / physiology
-
Smell / genetics
-
Tretinoin / metabolism
Substances
-
Receptors, Retinoic Acid
-
Tretinoin
-
Cytochrome P-450 Enzyme System
-
Retinoic Acid 4-Hydroxylase
-
Casp3 protein, mouse
-
Caspase 3
-
Caspases