A novel hypothyroid 'growth-retarded' mouse derived from Snell's dwarf mouse

Abstract

This paper describes a novel mutant mouse that has been spontaneously derived from the Snell's dwarf (DW/J) mouse. It was named the 'growth-retarded mouse' because of a characteristic growth pause followed by the delayed onset of pubertal growth. The onset of the increase in pituitary GH content that normally occurs concomitant with pubertal growth was also delayed in the growth-retarded mice. The serum concentration of thyroxine was very low in these mice from the neonatal period through adulthood, and a supplement of tri-iodothyronine was effective in shortening the growth pause and commencing the suppressed pubertal growth. Histological and immunohistochemical studies revealed that the anterior pituitary gland of the growth-retarded mouse contains clustered unusual chromophobic cells which are not reactive to various antisera against anterior pituitary hormones and the gland becomes enlarged with age. Breeding data indicated that these characteristics of the mice show an autosomal recessive inheritance and the gene responsible was designated as 'grm'. Partial linkage analysis utilizing microsatellite polymorphism demonstrated that the grm gene does not identify with the lit or hyt genes. Based on comparison of the hormonal status and growth pattern between growth-retarded, dwarf and normal mice, we have suggested the existence of a mutual interaction, possibly positive feedback regulation, between the pituitary and thyroid glands, that develops or matures the hormonal network which is responsible for rapid somatic growth and metabolic changes at puberty in mice.

Impaired insulin secretion from the pancreatic islets of hypothyroidal growth-retarded mice

“…T 3 replacement restores growth retardation (Yoshida et al 1994) and serum TSH levels (Tomita et al 1995) in grt mice. Thyroid hormone receptor a (TRa) and TRb mRNA and protein have been detected in pancreatic islets (Zinke et al 2003).…”

“…Normal phenotype (C/C or C/grt) and grt (grt/grt) male mice were obtained by mating wild (C/C) or heterozygous (C/grt) female mice with grt male mice. These mice were initially obtained as the offspring born to a pair of phenotypically normal siblings of DW/J strain mice and were distinguished on the basis of their body weights as described elsewhere (Yoshida et al 1994). Animals were studied at 2-12 months of age, and all experimental procedures were performed in accordance with the Institutional Guidelines for Animal Care and Use of Saitama University.…”

“…The growth-retarded (grt) mouse was first reported as a mutant spontaneously derived from phenotypically normal siblings of the Snell's dwarf mouse (DW/J strain) with a characteristic growth pause followed by delayed onset of pubertal growth in contrast to dw mice (Yoshida et al 1994). In grt mice, plasma concentrations of thyroxine (T 4 ) are significantly lower, whereas levels of thyroid-stimulating hormone (TSH) are greatly elevated (Yoshida et al 1994, Tomita et al 1995, Kobayashi et al 2001.…”

“…In grt mice, plasma concentrations of thyroxine (T 4 ) are significantly lower, whereas levels of thyroid-stimulating hormone (TSH) are greatly elevated (Yoshida et al 1994, Tomita et al 1995, Kobayashi et al 2001. The unresponsive nature of TSH receptors to TSH is considered to be attributable to dysfunction of the grt thyroid gland (Kobayashi et al 2001(Kobayashi et al , 2005.…”

Female Infertility in grt Mice is Caused by Thyroid Hormone Deficiency, not by Insufficient TPST2 Activity in the Reproductive Organs

“…Therefore, we concluded that the infertility in grt female is due to a thyroid hormone deficiency. The growth-retarded (grt) mouse has an autosomal recessive, fetal-onset, severe thyroid dysgenesis related to thyroid-stimulating hormone (TSH) hyporesponsiveness [20,41]. We identified that the grt phenotype is caused by a single misssense mutation in the tyrosylprotein sulfotransferase 2 (TPST2) gene with a C-to-G transition at nucleotide 798, leading to the replacement of a highly conserved histidine with glutamine at codon 266 in the sulfotransferase domain by positional cloning [36].…”