tretinoin and quinone

Stimulus-dependent expression of the retinoic acid-inactivating enzyme Cyp26B1 in olfactory sensory neurons (OSNs) forms a dorsomedial (DM)-ventrolateral (VL) gradient in the mouse olfactory epithelium. The gradient correlates spatially with different rates of OSN turnover, as well as the functional organization of the olfactory sensory map, into overlapping zones of OSNs that express different odorant receptors (ORs). Here, we analyze transgenic mice that, instead of a stimulus-dependent Cyp26B1 gradient, have constitutive Cyp26B1 levels in all OSNs. Starting postnatally, OSN differentiation is decreased and progenitor proliferation is increased. Initially, these effects are selective to the VL-most zone and correlate with reduced ATF5 expression and accumulation of OSNs that do not express ORs. Transcription factor ATF5 is known to stabilize OR gene choice via onset of the stimulus-transducing enzyme adenylyl cyclase type 3. During further postnatal development of Cyp26B1 mice, an anomalous DM(high)-VL(low) expression gradient of adenylyl cyclase type 3 appears, which coincides with altered OR frequencies and OR zones. All OR zones expand ventrolaterally except for the VL-most zone, which contracts. The expansion results in an increased zonal overlap that is also evident in the innervation pattern of OSN axon terminals in olfactory bulbs. These findings together identify a mechanism by which postnatal sensory-stimulated vitamin A metabolism modifies the generation of spatially specified neurons and their precise topographic connectivity. The distributed patterns of vitamin A-metabolizing enzymes in the nervous system suggest the possibility that the mechanism may also regulate neuroplasticity in circuits other than the olfactory sensory map.. The mouse olfactory sensory map is functionally wired according to precise axonal projections of spatially organized classes of olfactory sensory neurons in the nose. The genetically controlled mechanisms that regulate the development of the olfactory sensory map are beginning to be elucidated. Little is known about mechanisms by which sensory stimuli shape the organization of the map after birth. We show that a stimulus-dependent gradient of a retinoic acid-inactivating enzyme Cyp26B1 modifies the composition, localization, and axonal projections of olfactory sensory neuron classes. The mechanism is novel and suggests the interesting possibility that local vitamin A metabolism could also be a mediator of stimulus-dependent modifications of precise spatial connectivity in other parts of the nervous system.

Topics: Activating Transcription Factors; Age Factors; Aldehyde Dehydrogenase 1 Family; Animals; Animals, Newborn; Benzoquinones; beta-Galactosidase; Brain Mapping; Cell Differentiation; Cell Proliferation; Cytochrome P-450 Enzyme System; Gene Expression Regulation; Histones; Isoenzymes; Keratolytic Agents; Mice; Mice, Transgenic; Neural Cell Adhesion Molecules; Olfactory Marker Protein; Olfactory Mucosa; Retinal Dehydrogenase; Retinoic Acid 4-Hydroxylase; Sensory Receptor Cells; Tretinoin

Chronic exposure of humans to benzene has been shown to have a cytotoxic effect on hematopoietic progenitor cells in intermediate stages of differentiation, which can lead to aplastic anemia and acute myelogenous leukemia. We studied the effect of hydroquinone (HQ), a toxic metabolite of benzene found in the bone marrow, on the human promyelocytic leukemia cell line (HL-60), which can be induced to differentiate to both monocyte and myeloid cells, and thus has been used as a surrogate for a granulocyte/macrophage progenitor cell. Exposure of HL-60 cells to noncytotoxic concentrations of HQ for 3 hours before induction with phorbol myristate acetate (TPA) caused a dose-dependent inhibition of the acquisition of characteristics of monocytic differentiation, such as adherence, nonspecific esterase (NSE) activity, and phagocytosis, but had no effect on cell proliferation. HQ appeared to be affecting maturation beyond the monoblast/promonocyte stages. HQ also prevented differentiation induced by 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]; however, the block occurred after the acquisition of adherence. HQ at concentrations that inhibited monocytic differentiation had no effect on differentiation to granulocytes, suggesting that the block in the differentiation of these bipotential cells is a step unique to the monocytic pathway. HQ was unable to prevent differentiation induced by the macrophage-derived cytokine, interleukin (IL)-1, a differentiation factor for cells of the monocytic lineage.

Topics: Benzene Derivatives; Benzoquinones; Calcitriol; Cell Differentiation; Dose-Response Relationship, Drug; Granulocytes; Humans; Hydroquinones; In Vitro Techniques; Interleukin-1; Leukemia, Promyelocytic, Acute; Macrophages; Monocytes; Tetradecanoylphorbol Acetate; Tretinoin; Tumor Cells, Cultured