Glucocorticoid receptor activities in the zebrafish model: a review

Abstract

Glucocorticoids (GCs) are steroid hormones that contribute to the regulation of many physiological processes, such as inflammation, metabolism and stress response, mainly through binding to their cognate receptor, GR, which works as a ligand-activated transcription factor. Due to their pleiotropy and the common medical use of these steroids to treat patients affected by different pathologies, the investigation of their mechanisms of action is extremely important in biology and clinical research. The evolutionary conservation of GCs’ physiological functions, biosynthesis pathways as well as sequence and structure of their nuclear receptor, in the last 20 years has stimulated the use of zebrafish (a teleost of Ciprinidae family) as a reliable model organism to investigate the topic. In this review, we wanted to collect many of the most important discoveries that the scientific community has obtained using zebrafish to study GCs and their receptors. The paper begins by describing the experiments with transient knockdown of zebrafish gr to gain information mainly during development and continues with the discoveries provided by the generation of transgenic reporter lines. Finally, we discuss how the generation of mutant lines for either gr or the enzymes involved in GCs’ synthesis has significantly advanced our knowledge on GCs’ biology.

Long lasting anxiety following early life stress is dependent on glucocorticoid signaling in zebrafish

“…The glucocorticoid receptor, for example, has several isoforms. The GRα isoform is highly active while the GRβ is inert and can act as an inhibitor of GR signaling [83][84][85] . Alternatively, overactivation of GR alone may impair brain development.…”

Knockout of the hsd11b2 Gene Extends the Cortisol Stress Response in Both Zebrafish Larvae and Adults

“…In zebrafish, pre-vitellogenic follicles upregulate hsd11b2 after exposure to cortisol excess, suggesting the presence of a similar mechanism to protect embryo from abnormal levels of cortisol [23]. Since the advent of CRISPR/Cas9-targeted mutagenesis a great number of zebrafish mutant lines have been generated to improve our knowledge of glucocorticoid biology and functions, as reviewed in Dinarello and collaborators [24]. However, despite this growing number of studies, little is known about how the deactivation of Hsd11b2 affects zebrafish in terms of larval development, endocrine regulation of the stress response and behavior.…”

Glucocorticoid-Mediated Developmental Programming of Vertebrate Stress Responsivity

“…Several zebrafish mutants lacking functional GR have been produced (reviewed in Dinarello et al, 2020), which have the advantage of being viable throughout adulthood, in contrast to mammalian systems wherein loss of the receptor results in neonatal death through mechanisms previously described. Unsurprisingly however, lower survival has been noted in mutants at zygotic/embryonic (Gans et al, 2020;Maradonna et al, 2020) and post-larval stages (Facchinello et al, 2017).…”

“…With the advent of CRISPR, several laboratories have generated GR mutant zebrafish lines to further exploit the usefulness of zebrafish to investigate vertebrate GC signaling (Dinarello et al, 2020). Like the s357 strain, mutants with a 7-bp deletion in exon 2 leading to a truncated protein display hyper-cortisolemia.…”