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Long-distance retinoid signaling in the zebra finch brain.

Roeske TC, Scharff C, Olson CR, Nshdejan A, Mello CV - PLoS ONE (2014)

Bottom Line: Our results show that (1) ATRA is more broadly distributed in the brain than previously predicted by the spatially restricted distribution of zRalDH transcripts.This could be due to long-range transport of zRalDH enzyme between different nuclei of the song system: Experimental lesions of putative zRalDH peptide source regions diminish ATRA-induced transcription in target regions. (2) Four telencephalic song nuclei express different and specific subsets of retinoid-related receptors and could be targets of retinoid regulation; in the case of the lateral magnocellular nucleus of the anterior nidopallium (lMAN), receptor expression is dynamically regulated in a circadian and age-dependent manner. (3) High-order auditory areas exhibit a complex distribution of transcripts representing ATRA synthesizing and degrading enzymes and could also be a target of retinoid signaling.Together, our survey across multiple connected song nuclei and auditory brain regions underscores the prominent role of retinoid signaling in modulating the circuitry that underlies the acquisition and production of learned vocalizations.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, Hunter College, City University of New York, New York, New York, United States of America.

ABSTRACT
All-trans retinoic acid (ATRA), the main active metabolite of vitamin A, is a powerful signaling molecule that regulates large-scale morphogenetic processes during vertebrate embryonic development, but is also involved post-natally in regulating neural plasticity and cognition. In songbirds, it plays an important role in the maturation of learned song. The distribution of the ATRA-synthesizing enzyme, zRalDH, and of ATRA receptors (RARs) have been described, but information on the distribution of other components of the retinoid signaling pathway is still lacking. To address this gap, we have determined the expression patterns of two obligatory RAR co-receptors, the retinoid X receptors (RXR) α and γ, and of the three ATRA-degrading cytochromes CYP26A1, CYP26B1, and CYP26C1. We have also studied the distribution of zRalDH protein using immunohistochemistry, and generated a refined map of ATRA localization, using a modified reporter cell assay to examine entire brain sections. Our results show that (1) ATRA is more broadly distributed in the brain than previously predicted by the spatially restricted distribution of zRalDH transcripts. This could be due to long-range transport of zRalDH enzyme between different nuclei of the song system: Experimental lesions of putative zRalDH peptide source regions diminish ATRA-induced transcription in target regions. (2) Four telencephalic song nuclei express different and specific subsets of retinoid-related receptors and could be targets of retinoid regulation; in the case of the lateral magnocellular nucleus of the anterior nidopallium (lMAN), receptor expression is dynamically regulated in a circadian and age-dependent manner. (3) High-order auditory areas exhibit a complex distribution of transcripts representing ATRA synthesizing and degrading enzymes and could also be a target of retinoid signaling. Together, our survey across multiple connected song nuclei and auditory brain regions underscores the prominent role of retinoid signaling in modulating the circuitry that underlies the acquisition and production of learned vocalizations.

No MeSH data available.


Related in: MedlinePlus

Simplified schematic of the all-trans retinoic acid (ATRA) signaling pathway.ATRA is synthesized from retinol (Vitamin A) in a two-step oxidation process which takes place in the cytoplasm. To induce transcription, retinoic acid receptors (RARs) need to be activated by ATRA binding, and both RARs and retinoid X receptors (RXRs) need to bind retinoic acid response elements (RAREs) in the vicinity of target genes. Several CYP26 isoforms are responsible for ATRA degradation. Due to its small size and hydro- and lipophilic properties, ATRA is able to cross cell membranes and thus act in other cells.
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pone-0111722-g002: Simplified schematic of the all-trans retinoic acid (ATRA) signaling pathway.ATRA is synthesized from retinol (Vitamin A) in a two-step oxidation process which takes place in the cytoplasm. To induce transcription, retinoic acid receptors (RARs) need to be activated by ATRA binding, and both RARs and retinoid X receptors (RXRs) need to bind retinoic acid response elements (RAREs) in the vicinity of target genes. Several CYP26 isoforms are responsible for ATRA degradation. Due to its small size and hydro- and lipophilic properties, ATRA is able to cross cell membranes and thus act in other cells.

Mentions: The targets of ATRA in the brain are dependent on the distribution of its synthetic enzymes, target receptors and degradation enzymes which work in concert to locally control levels of ATRA, and knowing how these systems operate in the songbird brain would provide us an inference into how retinoid signaling may regulate the ability of a bird to learn its song. In the postnatal zebra finch brain ATRA activity has been associated with the expression of retinaldehyde-specific aldehyde dehydrogenase (zRalDH, a.k.a. RalDH2, or Aldh1a2 [21], see fig. 2). Yet, other enzymes can oxidize retinal to retinoic acid: aldehyde dehydrogenases RalDH1, RalDH3 and, as recently shown, a cytochrome, CYP1B1, can also mediate this reaction (see [1] for a review). Thus, while zRalDH is likely a good indicator of ATRA synthesis in the post-natal songbird brain, we cannot exclude the possible activity of other ATRA synthesizing enzymes whose brain expression patterns remain unknown. However, for HVC, a combination of immunodetection and enzyme kinetics methods has not revealed any evidence for the presence of multiple related ATRA synthesizing enzyme types [24], suggesting that zRalDH likely constitutes the major enzyme involved in ATRA synthesis in major song nuclei of the zebra finch brain. zRalDH mRNA in adult zebra finches is expressed in a very restricted pattern, primarily in HVC and in a rostral nidopallial band that includes lMAN [21], [25], [26]. This suggests that ATRA is produced at discrete brain sites, a possibility supported by evidence from cell reporter assays using tissue punches [21]. Local pharmacological blocking of zRalDH activity in the HVC of juvenile males disrupts normal song maturation, indicating a critical role for the ATRA synthesized in this song nucleus [21]. However, the exact sites of retinoid action relevant for song development are not known. Due to its hydro-lipophilic properties, ATRA can potentially reach brain areas several hundred micrometers away from its production sites [27], [28]. Consistent with this possibility, the brain distribution of the retinoic acid receptors (RARs) α, β, and γ, as determined by in situ hybridization (ISH), is very broad [29], and includes areas that are distant from sites of zRalDH expression. Importantly, RARs need to form heterodimers with another class of nuclear receptors, retinoid X receptors (RXRs), before they can act as transcriptional regulators upon binding of ATRA [30]–[34], as depicted in fig. 2. Thus, determining the distribution of RXRs is essential to identify actual target sites of ATRA signaling. Furthermore, the cytochromes CYP26A1, CYP26B1, and CYP26C1 are the main enzymes responsible for ATRA degradation (fig. 2) [35]–[37], thus their brain distribution limits the spatial extent of ATRA action.


Long-distance retinoid signaling in the zebra finch brain.

Roeske TC, Scharff C, Olson CR, Nshdejan A, Mello CV - PLoS ONE (2014)

Simplified schematic of the all-trans retinoic acid (ATRA) signaling pathway.ATRA is synthesized from retinol (Vitamin A) in a two-step oxidation process which takes place in the cytoplasm. To induce transcription, retinoic acid receptors (RARs) need to be activated by ATRA binding, and both RARs and retinoid X receptors (RXRs) need to bind retinoic acid response elements (RAREs) in the vicinity of target genes. Several CYP26 isoforms are responsible for ATRA degradation. Due to its small size and hydro- and lipophilic properties, ATRA is able to cross cell membranes and thus act in other cells.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230966&req=5

pone-0111722-g002: Simplified schematic of the all-trans retinoic acid (ATRA) signaling pathway.ATRA is synthesized from retinol (Vitamin A) in a two-step oxidation process which takes place in the cytoplasm. To induce transcription, retinoic acid receptors (RARs) need to be activated by ATRA binding, and both RARs and retinoid X receptors (RXRs) need to bind retinoic acid response elements (RAREs) in the vicinity of target genes. Several CYP26 isoforms are responsible for ATRA degradation. Due to its small size and hydro- and lipophilic properties, ATRA is able to cross cell membranes and thus act in other cells.
Mentions: The targets of ATRA in the brain are dependent on the distribution of its synthetic enzymes, target receptors and degradation enzymes which work in concert to locally control levels of ATRA, and knowing how these systems operate in the songbird brain would provide us an inference into how retinoid signaling may regulate the ability of a bird to learn its song. In the postnatal zebra finch brain ATRA activity has been associated with the expression of retinaldehyde-specific aldehyde dehydrogenase (zRalDH, a.k.a. RalDH2, or Aldh1a2 [21], see fig. 2). Yet, other enzymes can oxidize retinal to retinoic acid: aldehyde dehydrogenases RalDH1, RalDH3 and, as recently shown, a cytochrome, CYP1B1, can also mediate this reaction (see [1] for a review). Thus, while zRalDH is likely a good indicator of ATRA synthesis in the post-natal songbird brain, we cannot exclude the possible activity of other ATRA synthesizing enzymes whose brain expression patterns remain unknown. However, for HVC, a combination of immunodetection and enzyme kinetics methods has not revealed any evidence for the presence of multiple related ATRA synthesizing enzyme types [24], suggesting that zRalDH likely constitutes the major enzyme involved in ATRA synthesis in major song nuclei of the zebra finch brain. zRalDH mRNA in adult zebra finches is expressed in a very restricted pattern, primarily in HVC and in a rostral nidopallial band that includes lMAN [21], [25], [26]. This suggests that ATRA is produced at discrete brain sites, a possibility supported by evidence from cell reporter assays using tissue punches [21]. Local pharmacological blocking of zRalDH activity in the HVC of juvenile males disrupts normal song maturation, indicating a critical role for the ATRA synthesized in this song nucleus [21]. However, the exact sites of retinoid action relevant for song development are not known. Due to its hydro-lipophilic properties, ATRA can potentially reach brain areas several hundred micrometers away from its production sites [27], [28]. Consistent with this possibility, the brain distribution of the retinoic acid receptors (RARs) α, β, and γ, as determined by in situ hybridization (ISH), is very broad [29], and includes areas that are distant from sites of zRalDH expression. Importantly, RARs need to form heterodimers with another class of nuclear receptors, retinoid X receptors (RXRs), before they can act as transcriptional regulators upon binding of ATRA [30]–[34], as depicted in fig. 2. Thus, determining the distribution of RXRs is essential to identify actual target sites of ATRA signaling. Furthermore, the cytochromes CYP26A1, CYP26B1, and CYP26C1 are the main enzymes responsible for ATRA degradation (fig. 2) [35]–[37], thus their brain distribution limits the spatial extent of ATRA action.

Bottom Line: Our results show that (1) ATRA is more broadly distributed in the brain than previously predicted by the spatially restricted distribution of zRalDH transcripts.This could be due to long-range transport of zRalDH enzyme between different nuclei of the song system: Experimental lesions of putative zRalDH peptide source regions diminish ATRA-induced transcription in target regions. (2) Four telencephalic song nuclei express different and specific subsets of retinoid-related receptors and could be targets of retinoid regulation; in the case of the lateral magnocellular nucleus of the anterior nidopallium (lMAN), receptor expression is dynamically regulated in a circadian and age-dependent manner. (3) High-order auditory areas exhibit a complex distribution of transcripts representing ATRA synthesizing and degrading enzymes and could also be a target of retinoid signaling.Together, our survey across multiple connected song nuclei and auditory brain regions underscores the prominent role of retinoid signaling in modulating the circuitry that underlies the acquisition and production of learned vocalizations.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, Hunter College, City University of New York, New York, New York, United States of America.

ABSTRACT
All-trans retinoic acid (ATRA), the main active metabolite of vitamin A, is a powerful signaling molecule that regulates large-scale morphogenetic processes during vertebrate embryonic development, but is also involved post-natally in regulating neural plasticity and cognition. In songbirds, it plays an important role in the maturation of learned song. The distribution of the ATRA-synthesizing enzyme, zRalDH, and of ATRA receptors (RARs) have been described, but information on the distribution of other components of the retinoid signaling pathway is still lacking. To address this gap, we have determined the expression patterns of two obligatory RAR co-receptors, the retinoid X receptors (RXR) α and γ, and of the three ATRA-degrading cytochromes CYP26A1, CYP26B1, and CYP26C1. We have also studied the distribution of zRalDH protein using immunohistochemistry, and generated a refined map of ATRA localization, using a modified reporter cell assay to examine entire brain sections. Our results show that (1) ATRA is more broadly distributed in the brain than previously predicted by the spatially restricted distribution of zRalDH transcripts. This could be due to long-range transport of zRalDH enzyme between different nuclei of the song system: Experimental lesions of putative zRalDH peptide source regions diminish ATRA-induced transcription in target regions. (2) Four telencephalic song nuclei express different and specific subsets of retinoid-related receptors and could be targets of retinoid regulation; in the case of the lateral magnocellular nucleus of the anterior nidopallium (lMAN), receptor expression is dynamically regulated in a circadian and age-dependent manner. (3) High-order auditory areas exhibit a complex distribution of transcripts representing ATRA synthesizing and degrading enzymes and could also be a target of retinoid signaling. Together, our survey across multiple connected song nuclei and auditory brain regions underscores the prominent role of retinoid signaling in modulating the circuitry that underlies the acquisition and production of learned vocalizations.

No MeSH data available.


Related in: MedlinePlus