Abstract
Glucocorticoids (GCs) play important roles in developmental and physiological processes through the transcriptional activity of their cognate receptor (Gr). Using CRISPR/Cas9 technology, we established a zebrafish null Gr mutant line and compared its phenotypes with wild type and a zebrafish line with partially silenced gr (grs357/s357). Homozygous gr−/− larvae are morphologically inconspicuous and, in contrast to GR−/− knockout mice, viable through adulthood, although with reduced fitness and early life survival. Mutants gr−/− are fertile, but their reproductive capabilities fall at around 10 months of age, when, together with cardiac and intestinal abnormalities already visible at earlier stages, increased fat deposits are also observed. Mutants show higher levels of whole-body cortisol associated with overstimulated basal levels of crh and pomca transcripts along the HPI axis, which is unresponsive to a mechanical stressor. Transcriptional activity linked to immune response is also hampered in the gr−/− line: after intestinal damage by dextran sodium sulphate exposure, there are neither inflammatory nor anti-inflammatory cytokine gene responses, substantiating the hypothesis of a dual-action of the GC-GR complex on the immune system. Hence, the zebrafish gr mutant line appears as a useful tool to investigate Gr functions in an integrated in vivo model.
Highlights
Glucocorticoids (GCs), predominantly cortisol in humans and teleost fish, and corticosterone in rodents, are steroid hormones secreted by the adrenal cortex in mammals and the interrenal tissue of the head kidney in teleosts
After GC binding, GR translocates into the nucleus, where it directly binds to GC responsive elements (GREs) in the promoter region of target genes, regulating their transcription in positive or negative ways
The 5-nucleotide insertion resulted in a frameshift mutation that leads to a premature stop codon located upstream of DNA-binding domain (DBD)
Summary
Glucocorticoids (GCs), predominantly cortisol in humans and teleost fish, and corticosterone in rodents, are steroid hormones secreted by the adrenal cortex in mammals and the interrenal tissue of the head kidney in teleosts. These hormones regulate many physiological processes, including glucose homeostasis, intermediary metabolism[1], inflammatory[2] and stress responses. Equivalent in structure and expression level[11], but was lately found to differ in function, because it does not act as a dominant-negative inhibitor of zGrβ in either cultured cells or zebrafish larvae[12]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
