Retinoic Acid Receptor-Dependent Survival of Olfactory Sensory Neurons in Postnatal and Adult Mice

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 retrogradedriven 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.

Thyroid hormone activation of retinoic acid synthesis in hypothalamic tanycytes

“…RA has only recently been recognized to be active in the hypothalamus as a regulatory factor and the hypothalamus is one of the few brain regions in which RA functions, alongside regions such as the hippocampus and olfactory system (Goodman et al, 2012; Hagglund et al, 2006; Shearer et al, 2012a). However the importance of RA and its precursor, vitamin A, to control feeding and weight, was recognized much earlier.…”

Activated retinoid receptors are required for the migration and fate maintenance of subsets of cortical neurons

“…To determine the role of endogenous RA signaling in the developing cortex, we expressed the dominant-negative RA receptor RAR403 in E14.5 embryonic cortices by in utero electroporation. RAR403 is a version of human RARα that lacks the AF2 domain required for ligand-dependent activation and has been demonstrated to effectively abolish RA signaling in vitro and in vivo (Damm et al, 1993;Hägglund et al, 2006;Rajaii et al, 2008;Sockanathan et al, 2003). We electroporated bicistronic constructs that contained internal ribosomal entry site-green fluorescent protein (IRES-GFP) sequences downstream of RAR403 to facilitate the identification of electroporated cells by GFP expression (Fig.…”

“…We have ablated RA signaling in the cortex by in utero electroporation of RAR403 , a dominant-negative RAR that has been successfully employed to disrupt endogenous RA signaling pathways in avian and mouse models (Damm et al, 1993;Rajaii et al, 2008;Hägglund et al, 2006;Sockanathan et al, 2003). We find that RAR403 expression delays the migration of subsets of cortical neurons, and in addition causes late-born neurons to lose their initial identities and acquire positional and molecular profiles characteristic of layer II neurons.…”

Differential Regulation of Bcl‐xL Gene Expression by Corticosterone, Progesterone, and Retinoic Acid

“…In contrast, in naïve T-thymocytes, RA has been shown to increase bcl2a1 expression and decrease apoptosis without affecting the expression of Bcl-x L [45]. Retinoic acids have been shown to mediate cell survival response in neuroblastoma cells, neural crest cells, myeloid leukemia blasts, lung cancer cells, islet-epithelial cells, and olfactory sensory neurons [46–51]. In cardiomyocytes, high glucose induced apoptosis can be inhibited by RA in NF-κB dependent manner [52].…”