A mouse model with tamoxifen‐inducible thyrocyte‐specific cre recombinase activity

Undeutsch, Henriette; Löf, Christoffer; Offermanns, Stefan; Kero, Jukka

doi:10.1002/dvg.22740

Cited by 17 publications

(13 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Compound mice were obtained by combining the following alleles: BrafCA [40], Pik3caLat [41] and Thyroglobulin-CreERT2 [42]. Mutations were induced by 5 consecutive daily injections of 1 mg tamoxifen IP.…”

Section: Methodsmentioning

confidence: 99%

Combined MEK and Pi3′-kinase inhibition reveals synergy in targeting thyroid cancer in vitro and in vivo

et al. 2017

View full text Add to dashboard Cite

Anaplastic thyroid cancers and radioiodine resistant thyroid cancer are posing a major treat since surgery combined with Iodine131 therapy is ineffective on them. Small-molecule inhibitors are presenting a new hope for patients, but often lead to drug resistance in many cancers. Based on the major mutations found in thyroid cancer, we propose the combination of a MEK inhibitor and a Pi3′-kinase inhibitor in pre-clinical models. We used human thyroid cancer cell lines and genetically engineered double mutant BRAFV600E PIK3CAH1047R mice to evaluate the effect of both inhibitors separately or in combination in terms of proliferation and signaling in vitro; tumor burden, histology, cell death induction and tumor markers expression in vivo. The combination of MEK and Pi’3-kinase inhibition shows a synergistic effect in term of proliferation and apoptosis induction through Survivin down-regulation in vitro. We show for the first time the effects of the combination of a MEK inhibitor and Pi3′-kinase inhibitor in a genetically engineered mouse model of aggressively lethal thyroid cancer. In fine, the two drugs cooperate to promote tumor shrinkage by inducing a proliferation arrest and an elevation of apoptosis in vivo. Moreover, a phenotypic reversion is also observed with a partial restoration of normal thyroid marker transcription, and thyroid cancer marker expression reduction.In conclusion, combination therapy of MEK and Pi3′-kinase inhibition synergizes to target double mutant thyroid cancer in vitro and in vivo. This multidrug approach could readily be translated into clinical practice and bring new perspectives for the treatment of incurable thyroid carcinoma.

show abstract

Section: Methodsmentioning

confidence: 99%

Combined MEK and Pi3′-kinase inhibition reveals synergy in targeting thyroid cancer in vitro and in vivo

et al. 2017

View full text Add to dashboard Cite

show abstract

“…We generated DTIRKO mice by crossing IR/IGF‐1R double floxed mice with Tg‐Cre transgenic mice. Because Tg expression starts and folliculogenesis begins at embryonic day 15 (E15), this mouse model has utility for analyzing the role of IR and IGF‐1R in thyroid folliculogenesis after completion of thyrocyte differentiation . To examine potential contributions of the IR and IGF‐1R in thyroid organogenesis, we euthanized mice at postnatal day 2 (P2).…”

Section: Resultsmentioning

confidence: 99%

“… DTIRKO thyroids show a decrease in the expression of these genes and these changes likely account for follicular dysgenesis of DTIRKO thyroids. As endogenous Tg expression starts at E15 and Cre‐mediated recombination is therefore likely to begin before birth, Tg‐Cre mediated inactivation of IR/IGF‐1R is a suitable model for studying their roles in folliculogenesis, which normally occurs from E15 to E21 in the mouse. However, it should be pointed out that IR/IGF‐1R does not seem to regulate other transcription factors such as Nkx2–1, and Pax8, so that neonatal DTIRKO follicles could contain heterogeneous populations of cells with varying degrees of differentiation.…”

Section: Discussionmentioning

confidence: 99%

Thyrocyte‐specific deletion of insulin and IGF‐1 receptors induces papillary thyroid carcinoma‐like lesions through EGFR pathway activation

Ock

Ahn

Lee

et al. 2018

Intl Journal of Cancer

View full text Add to dashboard Cite

Insulin and insulin-like growth factor (IGF)-1 signaling in the thyroid are thought to be permissive for the coordinated regulation by thyroid-stimulating hormone (TSH) of thyrocyte proliferation and hormone production. However, the integrated role of insulin receptor (IR) and IGF-1 receptor (IGF-1R) in thyroid development and function has not been explored. Here, we generated thyrocyte-specific IR and IGF-1R double knockout (DTIRKO) mice to precisely evaluate the coordinated functions of these receptors in the thyroid of neonates and adults. Neonatal DTIRKO mice displayed smaller thyroids, paralleling defective folliculogenesis associated with repression of the thyroid-specific transcription factor Foxe1. By contrast, at postnatal day 14, absence of IR and IGF-1R paradoxically induced thyrocyte proliferation, which was mediated by mTOR-dependent signaling pathways. Furthermore, we found elevated production of TSH during the development of follicular hyperplasia at 8 weeks of age. By 50 weeks, all DTIRKO mice developed papillary thyroid carcinoma (PTC)-like lesions that correlated with induction of the ErbB pathway. Taken together, these data define a critical role for IR and IGF-1R in neonatal thyroid folliculogenesis. They also reveal an important reciprocal relationship between IR/IGF-1R and TSH/ErbB signaling in the pathogenesis of thyroid follicular hyperplasia and, possibly, of papillary carcinoma.

show abstract

“…In addition, Tg animals may segregate the integration patterns when mated with non-Tg animals [50,51]. Although heterozygous Cre expression mouse lines have been used to generate conditional gene targeting mouse models [52,53,54], the sustained analysis of Cre integration patterns and expression in subsequent generations may be required for further applications of the AQP2-Cre Tg mini-pigs. Furthermore, the identified integration sites were shown to be on distinct genome loci in this study.…”

Section: Discussionmentioning

confidence: 99%

Expression of Cre Recombinase in Alveolar Epithelial Cells of the AQP2-Cre Transgenic Mini-Pigs

Luo

Huang

et al. 2014

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Optimal use of Cre mediated recombination in conditional animal models depends on well characterized Cre driver lines. Unfortunately, some Cre driver lines exhibit unexpected expression patterns hindering their utility in Cre/loxP systems. Thus, systematic assessment of new Cre lines is essential for generating useful Cre driver lines for future studies. Methods: Here, we describe a Cre Transgenic (Tg) mini-pig line in which the expression of Cre is directed by a 3-kb 5' fragment of the kidney-specific aquaporin 2 (AQP2); however, the AQP2-Cre Tg mini-pig line exhibits expression of Cre in alveolar epithelial cells (AECs) instead of collecting duct cells. The specificity of the AQP2-Cre plasmid was validated in vitro, and indicating that the AQP2-Cre was specifically expressed in the transfected LLC-PK1 cells. Absolute quantitative real-time PCR (qRT-PCR) and inverse PCR were performed to determine the copy numbers and integration sites of the AQP2-Cre transgene. Relative qRT-PCR was performed to evaluate variation in Cre expression levels over time. Results: Our data indicated that this AQP2-Cre Tg mini-pig line exhibits stable expression of Cre recombinase over time and in subsequent generations, even though the AQP2-Cre transgene was segregated and reduced in subsequent generations. Conclusion: Combined with our previous studies of the activity of this Cre, we conclude that this Cre Tg mini-pig line will provide a reliable tool for generating lung-specific gene targeting mini-pig models, thereby allowing the investigation of gene functions in lung development and studying the molecular mechanisms of human lung disease.

show abstract

A mouse model with tamoxifen‐inducible thyrocyte‐specific cre recombinase activity

Cited by 17 publications

References 20 publications

Combined MEK and Pi3′-kinase inhibition reveals synergy in targeting thyroid cancer in vitro and in vivo

Combined MEK and Pi3′-kinase inhibition reveals synergy in targeting thyroid cancer in vitro and in vivo

Thyrocyte‐specific deletion of insulin and IGF‐1 receptors induces papillary thyroid carcinoma‐like lesions through EGFR pathway activation

Expression of Cre Recombinase in Alveolar Epithelial Cells of the AQP2-Cre Transgenic Mini-Pigs

Contact Info

Product

Resources

About