Genetically engineered mouse models of FK506‐binding protein 5

Gebru, Niat T.; Hill, Shannon E.; Blair, Laura J.

doi:10.1002/jcb.30374

Cited by 3 publications

(1 citation statement)

References 117 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To explore biological functions of FKBP51, several mouse models have been generated including Fkbp5 complete and conditional knockouts, overexpression and humanized mouse models (for a recent review see [ 8 ]). Of them, Fkbp5 knockout (KO) mice were the most studied.…”

Section: Introductionmentioning

confidence: 99%

FKBP51-Hsp90 Interaction-Deficient Mice Exhibit Altered Endocrine Stress Response and Sex Differences Under High-Fat Diet

Wang,

Wojcieszak,

Kumar

et al. 2023

Mol Neurobiol

View full text Add to dashboard Cite

FK506-binding protein 51 kDa (FKBP51), encoded by Fkbp5 gene, gained considerable attention as an important regulator of several aspects of human biology including stress response, metabolic dysfunction, inflammation, and age-dependent neurodegeneration. Its catalytic peptidyl-prolyl isomerase (PPIase) activity is mediated by the N-terminal FK506-binding (FK1) domain, whereas the C-terminal tetratricopeptide motif (TPR) domain is responsible for FKBP51 interaction with molecular chaperone heat shock protein 90 (Hsp90). To understand FKBP51-related biology, several mouse models have been created. These include Fkbp5 complete and conditional knockouts, overexpression, and humanized models. To dissect the role of FKBP51-Hsp90 interaction in FKBP51 biology, we have created an interaction-deficient mouse (Fkbp5TPRmut) by introducing two-point mutations in the TPR domain of FKBP51. FKBP51-Hsp90 interaction-deficient mice are viable, fertile and show Mendelian inheritance. Intracellular association of FKBP51 with Hsp90 is significantly reduced in homozygous mutants compared to wild-type animals. No behavioral differences between genotypes were seen at 2 months of age, however, sex-dependent differences were detected in Y-maze and fear conditioning tests at the age of 12 months. Moreover, we have found a significant reduction in plasma levels of corticosterone and adrenocorticotropic hormone in Fkbp5TPRmut mice after acute stress. In contrast to Fkbp5 knockout mice, females of Fkbp5TPRmut showed increased body weight gain under high-fat diet treatment. Our data confirm the importance of FKBP51-Hsp90 interactions for stress-related endocrine signaling. Also, Fkbp5TPRmut mice can serve as a useful in vivo tool to discriminate between Hsp90-dependent and independent functions of FKBP51.

show abstract

Section: Introductionmentioning

confidence: 99%

FKBP51-Hsp90 Interaction-Deficient Mice Exhibit Altered Endocrine Stress Response and Sex Differences Under High-Fat Diet

Wang,

Wojcieszak,

Kumar

et al. 2023

Mol Neurobiol

View full text Add to dashboard Cite

show abstract

FKBP51 Overexpression in the Corticolimbic System Stabilizes Circadian Rhythms

Gebru,

Beaulieu-Abdelahad,

Gulick

et al. 2024

Cell Stress and Chaperones

View full text Add to dashboard Cite

DNA methylation patterns of FKBP5 regulatory regions in brain and blood of humanized mice and humans

Yusupov,

Roeh,

Sotillos Elliott

et al. 2024

Mol Psychiatry

View full text Add to dashboard Cite

Humanized mouse models can be used to explore human gene regulatory elements (REs), which frequently lie in non-coding and less conserved genomic regions. Epigenetic modifications of gene REs, also in the context of gene x environment interactions, have not yet been explored in humanized mouse models. We applied high-accuracy measurement of DNA methylation (DNAm) via targeted bisulfite sequencing (HAM-TBS) to investigate DNAm in three tissues/brain regions (blood, prefrontal cortex and hippocampus) of mice carrying the human FK506-binding protein 5 (FKBP5) gene, an important candidate gene associated with stress-related psychiatric disorders. We explored DNAm in three functional intronic glucocorticoid-responsive elements (at introns 2, 5, and 7) of FKBP5 at baseline, in cases of differing genotype (rs1360780 single nucleotide polymorphism), and following application of the synthetic glucocorticoid dexamethasone. We compared DNAm patterns in the humanized mouse (N = 58) to those in human peripheral blood (N = 447 and N = 89) and human postmortem brain prefrontal cortex (N = 86). Overall, DNAm patterns in the humanized mouse model seem to recapitulate DNAm patterns observed in human tissue. At baseline, this was to a higher extent in brain tissue. The animal model also recapitulated effects of dexamethasone on DNAm, especially in peripheral blood and to a lesser extent effects of genotype on DNAm. The humanized mouse model could thus assist in reverse translation of human findings in psychiatry that involve genetic and epigenetic regulation in non-coding elements.

show abstract

Genetically engineered mouse models of FK506‐binding protein 5

Cited by 3 publications

References 117 publications

FKBP51-Hsp90 Interaction-Deficient Mice Exhibit Altered Endocrine Stress Response and Sex Differences Under High-Fat Diet

FKBP51-Hsp90 Interaction-Deficient Mice Exhibit Altered Endocrine Stress Response and Sex Differences Under High-Fat Diet

FKBP51 Overexpression in the Corticolimbic System Stabilizes Circadian Rhythms

DNA methylation patterns of FKBP5 regulatory regions in brain and blood of humanized mice and humans

Contact Info

Product

Resources

About