3.1.1. Mouse Models

In 2004, Griffin et al. generated a mouse model carrying an antisense transgene for *Prkar1a* exon 2 (X2AS) under the control of a tetracycline responsive promoter (the Tg(Prakr1a\*x2as)1Stra, Tg(tTAhCMV)3Uh, or tTA/X2AS) [45]. Increased cAMP signaling was demonstrated due to significant *Prkar1a* downregulation and the mice exhibited a more severe phenotype with high incidence of thyroid lesions (thyroid follicular hyperplasia and adenomas). This was an extremely rare finding in wild type animals but quite common in those with the genetic defect (as it is common among patients with CNC). Furthermore, the lesions were associated with allelic loss of the *Prkar1a* locus on chromosome 11 as it happens in thyroid tumors with *PRKAR1A* mutations. Moreover, tumor tissues demonstrated an increase in the activity of type II PKA and higher RIIβ levels, an abnormal cAMP response.

In a later study, *Prkar1a* haploinsufficiency in mice was investigated. It was shown that *Prkar1a* haploinsufficiency leads to tumor development arising in cAMP-responsive tissues, including among others, benign and malignant thyroid neoplasms [41]. Mice heterozygous for a conventional null allele of *Prkar1a* (*Prkar1a*Δ2/+ mice) were generated. These mice developed tumors in the same spectrum as CNC patients. Thyroid neoplasms were present in 10% of *Prkar1a*Δ2/+ mice [41]. In addition, allelic loss occurred in a portion of tumor cells, as indicated by genetic analysis, suggesting that complete loss of *Prkar1a* plays a vital role in tumor formation.

A different mouse model, carrying a thyroid-specific deletion of *Prkar1a* (Tpo-R1αKO) was studied [46]. In 43% of mice, FTC was observed by 1 year of age. However, distant hematogenous metastases were not present, which is a key feature of FTC in humans [46]; this could potentially suggest that metastases may be triggered by another genetic mutation in the case of *Prkar1a* mutation in the thyroid. An interesting observation by the authors was that thyroid ablation of *PRKAR1A/Prkar1a* is the only genetic change that has been described that results in FTC in both mice and humans.
