Abstract
Our recent transcriptome analysis1 found that apoc1, which encodes an apolipoprotein with poorly understood central nervous system function, is highly expressed by zebrafish microglia. We became interested in microglial expression of this gene because, APOC1 has been shown to have genetic association with human neurodegenerative diseases. Even with disease association, very little is known about the function of Apoc1 in the central nervous system. In fact, microglia-specific expression of this gene, or whether expression is developmentally regulated, has yet to be definitively demonstrated.
First, we examined the orthologous relationship between human APOC1 and zebrafish apoc1 and concluded that these genes are orthologous. We characterized expression patterns of apoc1 in the developing zebrafish central nervous system using anti-sense RNA probe. Apoc1 transcript was localized to microglia in 3- and 5-day old zebrafish retina and brain. There was a dramatic increase in in apoc1 transcripts on a per microglial cell basis during development as well. We also found that apoc1 mRNA localized exclusively to microglia in adult zebrafish retinas.
To provide insight into the regulation of apoc1 expression in microglia, we performed in silico analysis of the 5’ UTR and a 5kb sequence upstream of the predicted zebrafish apoc1 start site. The transcription factor (TF) binding site analysis indicated that the 5kb region upstream of apoc1 contains several predicted TF binding sites. We identified TF binding sites included those for RAR:RXR and PPARα:RXR. We therefore hypothesized that the ligands for RAR:RXR and/or PPAR:RXR nuclear receptors may modulate expression of apoc1. Using agonists of these nuclear hormone receptors, we found that apoc1 expression can be upregulated in an RXR dependent manner, but that this RXR mediated induction does not involve the RAR binding partner.
Future experiments will aim to reveal the function of apoc1 expression by microglia in the CNS and its regulation. Understanding this gene may lead to further discoveries in its role in the CNS and may lead to treatments for neurodegenerative diseases.