Consequences of thyroid hormone deficiency induced by the specific ablation of thyroid follicle cells in adult transgenic mice.
The herpes simplex type 1 virus thymidine kinase (HSV1-TK) reporter gene was coupled to a bovine thyroglobulin promoter (TG-tk construct). Within the thyroid glands of transgenic mice expression was confined to thyroid follicle cells. Infusion of Ganciclovir (9-[(1,3-dihydroxy-2-propoxy)methyl]guanine) to 8 to 12 week transgenic females led to the complete loss of thyroid HSV1-TK activity (at 3 to 4 days) and thyroid follicles (between 7 and 14 days). During the first 5 days of treatment a single reciprocal oscillation in circulating thyroxine (T4) and TSH levels occurred. By 14 days the circulating tri-iodothyronine (T3) and T4 levels of all treated animals were below the detection limits of the assays, while TSH levels were elevated ten-fold and continued to increase thereafter. During 14 days of treatment the thyroids regressed, protein content fell by 80-90% and the C cells, normally dispersed within the central region of each gland, came together in aggregates. Pituitary GH levels in females rose and fell back to normal within 14 days and between 14 and 28 days fell to a level comparable with that of GH-deficient lit/lit mice. The levels of hepatic GH receptor mRNA and the predominant 6.6 kb T3 receptor mRNA were unaffected by thyrocyte ablation. Thyrocyte ablation had no effect on the level of prolactin (Prl) receptor mRNA in females, but increased Prl receptor mRNA levels in males and eliminated group 1 major urinary protein (MUP).mRNA in females. T4 replacement reversed the effects of thyrocyte ablation on MUP mRNA in females and on Prl receptor mRNA in males.2+ Despite the many physiological changes induced by thyrocyte ablation, ablated mice have been maintained for up to 1 year without thyroid hormone supplementation. T4-deficient females were normally fertile and carried pups to term. Although transgenic males expressed HSV1-TK ectopically in spermatids and spermatozoa at levels similar to thyrocyte levels, a rate of Ganciclovir infusion which successfully ablated the thyrocytes did not affect the testis. As an alternative to infusion by minipump, thyrocyte ablation could be achieved by 6 twice-daily injections of Ganciclovir, at a level of 112 micrograms Ganciclovir/g body weight per day, and fetuses in utero could be thyrocyte ablated by administering 50 or 15 micrograms/g body weight per day to pregnant females between days 14 and 18 of gestation. These data demonstrate the potential value of transgenic thyrocyte ablation in the study of the effects of thyroid hormone deprivation.
Centre for Genome Research, University of Edinburgh, UK.
H
H
Wallace
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K
McLaren
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R
al-Shawi
J O
JO
Bishop
D000818:Animals; D001483:Base Sequence; D004195:Disease Models, Animal; D005260:Female; D015774:Ganciclovir / Q000494:pharmacology; D015870:Gene Expression; D017930:Genes, Reporter; D013006:Growth Hormone / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010902:Pituitary Gland / Q000378:metabolism; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D011981:Receptors, Prolactin / Q000235:genetics; D018139:Simplexvirus / Q000201:enzymology; D013094:Spermatozoa / Q000502:physiology; D013937:Thymidine Kinase / Q000235:genetics; D013961:Thyroid Gland / Q000166:cytology / Q000502:physiology*; D013963:Thyroid Hormones / Q000172:deficiency*
D011506:Proteins; D012333:RNA, Messenger; D011981:Receptors, Prolactin; D013963:Thyroid Hormones; C035737:major urinary proteins; D013006:Growth Hormone; D013937:Thymidine Kinase; D015774:Ganciclovir