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