THE EVOLUTION OF THE D2 DOPAMINE RECEPTOR: ITS UNIQUE PROPERTIES AND ALTERNATIVE SPLICING IN THE VERTEBRATE BRAIN, THE AVIAN SONG SYSTEM, AND POSSIBLE FUNCTIONS OF THE CONSERVED MIR-9 SITES

The D2 dopamine receptor has roles in the regulation of physiology and behavior and is also involved in the pathophysiology and treatment of psychiatric diseases. Alternative splicing of Drd2 pre-mRNA produces D2 long “D2L”, and D2 short “D2S” receptors by exon skipping of exon 6. This splice choice alters cytoplasmic loop 3 of the D2 protein, and affects the rates of D2 endocytosis and cytoplasmic processing. Here it is shown that Drd2 exon 6 originated prior to the duplication and divergence of D2 and D3 dopamine receptor genes. The exon 6 homolog inherited by the Drd3 gene has not been well conserved and is not skipped during RNA splicing in any tetrapod species. Moreover, skipping of Drd2 exon 6 was not detectable in the brains of primitive aquatic vertebrates, nor in the primitive species of each tetrapod class. But Drd2 exon 6 was found to be skipped in the more derived species of each tetrapod class, suggesting that alterations of cytoplasmic loop 3 of the D2 receptor have been associated with adaptive radiations. Additional Drd2 mRNA isoforms were found in passeriform birds. In zebra finch (a passeriform bird), all Drd2 mRNA isoforms (including the passeriform-specific D2L-50 and D2S-50 variants) were present at higher levels in the anterior forebrain pathway of the song system than in any other brain area except the ventral striatum (which likely is also involved in song learning). These isoforms were relatively abundant in whole brain tissues of many other passerine species, but were rare or undetectable in all non-passerine bird species tested. This suggests that the -50 variants may help to facilitate song learning in passerine birds. Finally, in addition to exon 6, another unique property of Drd2 is the presence of a conserved miR-9 recognition site in the 3’ untranslated region. The functions and expression patterns of Drd2 are complex. A simpler case may be present in the Clock gene, which has multiple conserved miR-9 sites. Here it is shown that miR-9 expression and Clock expression were positively correlated with each other in two different vertebrate species and tissues. The evolutionary conservation of multiple miR-9 sites in the Clock mRNA must increase the turnover of Clock mRNA, but it evidently does so without altering the circadian expression pattern of Clock. That miRNAs encoded the turnover rates of targeted mRNAs rather than their expression patterns may prove to be a general paradigm for the interactions of many miRNAs with their target genes.

Author

• Peglar, Michael Thomas

• Alternative splicing
• Birdsong
• Circadian rhythms
• Dopamine receptors
• Evolution
• miRNA miR-9

Identifier

hdl:1920/13757

OAI identifier oai:identifier

oai:MARS:1920/13757