Table 1. Summary of Wnt/β-catenin LOF and GOF mouse models.
Spatiotemporal control of Wnt/β-catenin signaling is essential for proper development and homeostatic renewal in the adrenal cortex.
| Model | Cre driver | Cre activation | Cell population targeted | Allele | Result of recombination | Change in Wnt/β-catenin activation | Phenotype | Age | References |
|---|---|---|---|---|---|---|---|---|---|
| β-catenin LOF | SF1-Crehigh | E10.5 | Entire adrenal cortex | Ctnnb1tm2kem | Loss of β-catenin | Loss of β-catenin (IHC) | Adrenal hypoplasia progressing to aplasia | E12.5, E14.5, E16.5, and E18.5 | Kim et al 2008, Development |
| SF1-Crehigh | E10.5 | Entire adrenal cortex | Ctnnb1tm2kem | Loss of β-catenin | Data not shown | Adrenal hypoplasia progressing to aplasia | E16.5, E18.5, and P0 | Huang et al 2012, Molecular and Cellular Endocrinology | |
| SF1-Crelow | E10.5 | Stochastic within cortex | Ctnnb1tm2kem | Loss of β-catenin | Reduced TCF/LEF-LacZ and Axin2 (qPCR) | Progressive thinning of adrenal cortex | 15, 30, and 45 weeks of age | Kim et al 2008, Development | |
| RSPO3 LOF | cCAG:CreERT | +tamoxifen | Ubiquitous | Rspo3Fx/Fx | Loss of Rspo3 | Reduced Axin2 (qPCR) and Wnt4 (ISH) | Reduced cortical cell number and adrenal weight Loss of zG differentiation (DAB2 and CYP11B2) and loss of Shh and Gli1 expression | E16.5 (tamoxifen @ E11.5). 1 day or 2-, 4-, and 6-weeks post tamoxifen in adult mice. | Vidal et al, 2016, Genes and Development |
| Gli1:CreERT2 | +tamoxifen | Gli1+ capsular cells | Rspo3Fx/Fx | Loss of Rspo3 | Reduced Axin2 (qPCR) | Reduced adrenal weight Loss of zG differentiation (DAB2) | E18.5 (tamoxifen @ E13.5). 4 weeks post tamoxifen in adult mice. | Vidal et al, 2016, Genes and Development | |
| WNT4 LOF | SF1-Crehigh | E10.5 | Entire adrenal cortex | Wnt4Fx/Fx | Loss of Wnt4 | Reduced β-catenin (IHC), LEF1 (IHC and qPCR) and Axin2 (qPCR) | Mildly reduced adrenal weight Reduced expression of CYP11B2 and Agtr1 | 12 weeks of age | Drelon et al 2016, Nature Communications; Vidal et al, 2016, Genes and Development |
| N/A | N/A | Global knockout | Wnt4 global knockout | Global loss of Wnt4 | Data not shown | No change in adrenal size Reduced CYP11B2 expression and aldosterone production | E14.5, E18.5, and newborn | Heikkila et al 2002, Endocrinology | |
| PORCN LOF | SF1-Crehigh | E10.5 | Entire adrenal cortex | PorcnFx/Fx | Loss of Porcn | Data not shown | No change in adrenal size or proliferation Reduced DAB2 and increased AKR1B7 | 6 weeks of age | Basham et al, 2019, Genes and Development |
| RSPO1 LOF | N/A | N/A | Global knockout | Rspo1 global knockout | Global loss of Rspo1 | No change | No defect in adrenal weight or zonation | 4, 15, and 30 weeks of age | Vidal et al, 2016, Genes and Development |
| RNF43 LOF | SF1-Crehigh | E10.5 | Entire adrenal cortex | Rnf43Fx/Fx | Loss of Rnf43 | No change | No defect | 6 weeks of age | Basham et al, 2019, Genes and Development |
| ZNRF3 LOF | SF1-Crehigh | E10.5 | Entire adrenal cortex | Znrf3Fx/Fx | Loss of Znrf3 | Increased low-level β-catenin (IHC), Axin2 and Wnt4 (RNAscope) | Progressive hyperplasia from P0 to 6 weeks. ~8.5-fold increased adrenal weight by 6 weeks | P0, P14, and 6 weeks of age | Basham et al, 2019, Genes and Development |
| ASCre/+ | E18.5 | Cyp11b2+ glomerulosa | Znrf3Fx/Fx | Loss of Znrf3 | Increased low-level Axin2 and Wnt4 (RNAscope) | Progressive hyperplasia after 15 weeks. ~5.5-fold increased adrenal weight by 52 weeks | 15, 30, and 52 weeks of age | Basham et al, 2019, Genes and Development | |
| β-catenin GOF | SF1-Crelow | E10.5 | Stochastic within cortex | ApcFx/Fx | Loss of Apc | Increased β-catenin (W. blot and IHC), Axin2 and Lef1 (qPCR) | Increased proliferation with no change in adrenal weight Progressive dysplasia | 15, 30, 45, and >45 weeeks of age | Heaton et al 2012, American Journal of Pathology |
| 0.5 akr1b7:Cre | E14.5 | Stochastic within cortex | Catnblox(ex3) | β-catenin stabilization | Increased β-catenin (W. blot and IHC) and Axin2 (qPCR) | Variable increase in proliferation with ~1.5-fold increased adrenal weight (10 months) Enhanced zG differentiation (increased CYP11B2 and aldosterone) | 5 months (~20 weeks) and 10 months (~40 weeks) | Berthon et al 2010, Human Molecular Genetics | |
| ASCre/+ | E18.5 | Cyp11b2+ glomerulosa | Catnblox(ex3) | β-catenin stabilization | Increased β-catenin (IF), Axin2 and Lef1 (qPCR) | No increase in proliferation. No increase in adrenal weight until after 38 weeks of age (~2-fold) Block in lineage conversion from zG to zF with increased aldosterone production | 5, 10, 15–21, and 38–53 weeks of age | Ling and Pignatti et al 2020, Nature Communications; Pignatti and Ling et al 2020, Cell Reports | |
| ASCre/Cre | E18.5 | Cyp11b2+ glomerulosa | Catnblox(ex3) | β-catenin stabilization | Increased β-catenin (IF) | Increased zG proliferation and increased adrenal weight (~2-fold) zG expansion not rescued by candesartan | Adult (age not specified) | Pignatti and Ling et al 2020, Cell Reports | |
| SF1-Crehigh | E10.5 | Entire adrenal cortex | Catnblox(ex3) | β-catenin stabilization | Data not shown | Significant adrenal hypoplasia | Timecourse from E16.5 to P21 | Huang et al 2012, Molecular and Cellular Endocrinology | |
| SF1-Crehigh | E10.5 | Entire adrenal cortex | Catnblox(ex3) | β-catenin stabilization | Data not shown | Significant left adrenal hypoplasia and right adrenal agenesis | 1 month of age (~4 weeks) | Drelon et al 2016, Nature Communications | |
| SF1-Crehigh | E10.5 | Entire adrenal cortex | ApcFx/Fx | Loss of Apc | Data not shown | Significant adrenal hypoplasia | E16.5 | Heaton et al 2012, American Journal of Pathology | |