Abstract Title

Effects of Selected Modulators of RXR Receptors on Microglial Apolipoprotein Expression During Early CNS Development

Additional Funding Sources

The project described was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under Grant No. P20GM103408 and Mitchell Lab funding: NIH Grant No. EY030467.

Abstract

The apolipoprotein genes are clustered within a chromosomal region in vertebrates called the apolipoprotein gene cluster. Of these genes, APOE and APOC1 are genetically associated with human neurodegenerative disease. In addition, these two genes and are considered to be part of a set of “Disease-Associated Microglia” genes, which are genes upregulated in microglial cells in contexts of neurodegeneration. Zebrafish orthologs of human APOE and APOC1 are apoeb and apoc1.

Microglia are resident macrophages in the central nervous system (CNS) of vertebrates. In our transcriptome analysis of sorted zebrafish microglia, apoc1 was our top hit of the microglia-enriched genes (1). This was interesting to us because Apoe expression by microglia is well appreciated, but Apoc1 expression by microglia has not been well-examined.

Interestingly, Gosselin et al. 2017 (2) showed RNA-seq that APOC1 is highly expressed by human microglia with comparatively lower expression by mouse microglia. This indicates that zebrafish are a justified model organism to study regulation and function of this gene.

PPAR//RXR and LXR/RXR receptors have been shown to regulate expression of the apolipoprotein gene cluster in other macrophages, but a similar role in microglia in an in vivo system has not been studied.

The zebrafish allows us to use a pharmacological approach to modulate PPAR, LXR, and RXR activity by immersion of fish in compounds during early development.

This allowed us to examine the role of these particular nuclear hormone receptors in regulation of microglial expression of apoc1 and apoeb during development of the central nervous system in a vertebrate animal.

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Effects of Selected Modulators of RXR Receptors on Microglial Apolipoprotein Expression During Early CNS Development

The apolipoprotein genes are clustered within a chromosomal region in vertebrates called the apolipoprotein gene cluster. Of these genes, APOE and APOC1 are genetically associated with human neurodegenerative disease. In addition, these two genes and are considered to be part of a set of “Disease-Associated Microglia” genes, which are genes upregulated in microglial cells in contexts of neurodegeneration. Zebrafish orthologs of human APOE and APOC1 are apoeb and apoc1.

Microglia are resident macrophages in the central nervous system (CNS) of vertebrates. In our transcriptome analysis of sorted zebrafish microglia, apoc1 was our top hit of the microglia-enriched genes (1). This was interesting to us because Apoe expression by microglia is well appreciated, but Apoc1 expression by microglia has not been well-examined.

Interestingly, Gosselin et al. 2017 (2) showed RNA-seq that APOC1 is highly expressed by human microglia with comparatively lower expression by mouse microglia. This indicates that zebrafish are a justified model organism to study regulation and function of this gene.

PPAR//RXR and LXR/RXR receptors have been shown to regulate expression of the apolipoprotein gene cluster in other macrophages, but a similar role in microglia in an in vivo system has not been studied.

The zebrafish allows us to use a pharmacological approach to modulate PPAR, LXR, and RXR activity by immersion of fish in compounds during early development.

This allowed us to examine the role of these particular nuclear hormone receptors in regulation of microglial expression of apoc1 and apoeb during development of the central nervous system in a vertebrate animal.