Postnatal Development of Hypoplastic Thymus in Semi-Lethal Dwarf pet/pet Males

Abstract

ABSTRACT. The petit rat (pet/pet) is a new semi-lethal dwarf mutant with anomalies in the thymus and testes, defects inherited as a single autosomal recessive trait. At birth, these pet/pet rats show low birth weight and extremely small thymuses; at 140 days of age, their thymuses show abnormal involution. In the present study, we examined early postnatal development of hypoplastic pet/pet thymuses. In addition to being hypoplastic at birth, pet/pet thymus growth was almost completely impaired during the early postnatal period. As shown by cellular incorporation of BrdU, the mitotic activity was lower in pet/pet than in normal thymuses, and terminal deoxynucleotidyl transferase dUTP nick end labeling assays showed that apoptosis occurred more often in pet/pet than in normal thymus cells during the first few days after birth. These results indicate that postnatal development of the hypoplastic pet/pet thymus is defective due to the reduced proliferation and increased apoptosis of thymic cells. The rodent thymus develops as a thymic primordium from the endoderm of the third pharyngeal pouch and from the mesenchyme of the neural crest derived from the third and fourth pharyngeal pouches [7]. Postnatally, the thymus increases in size, with expansion of the cortex and medulla, reaching a maximum size at around 10 weeks of age. Following sexual maturation, the thymus begins to shrink, and its weight and volume gradually decrease thereafter [1, 2].We have previously described pet/pet rats of the PET strain; these rats are characterized by postnatal semi-lethality, severe dwarfism from birth, testis anomalies, and markedly small thymuses (Fig. 1), all of which are controlled by a recessive mutation (pet) [4]. Newborn pet/pet rats were smaller in size, and they had very small thymuses. Relative weights (absolute weight/brain weight) of various organs were significantly lower in 140-day-old pet/pet rats than in age-matched normal rats, whereas the thymus was especially smaller in the former. Histologically, 140 day-old pet/pet thymuses contained both cortex and medulla compartments, but both were quite small, and abnormal thymic follicles were observed in the subcapsular region [4]. Because pet/pet thymuses are smaller at birth and degenerate earlier than normal thymuses, we examined the postnatal development of pet/pet thymuses in the present study.All experimental procedures and care of animals were performed in accordance with the guidelines of the Animal Care Committee of Nippon Veterinary and Life Science University. We utilized pet/pet male rats, identified by their low birth weight, and normal (+/pet or +/+) males of the PET strain; all animals were fed and maintained in our laboratory as described in a previous report [4]. At least 4 pet/ pet and normal males each were euthanized by ether overdoses at 0, 1, 3, 7, 12, and 21 days of age. Thymuses were removed from all rats, weighed, fixed in 10% phosphatebuffered formalin, and processed for paraffin sectioning as described previously [4,9,11]. Sections (thickness, ...

Characterization of Novel Nonobese Type 2 Diabetes Rat Model with Enlarged Kidneys

“…We characterized the phenotype of affected offspring rats and named the strain DEK. The pet locus is responsible for dwarfism, thymus hypoplasia, and postnatal semilethality [14, 15]. We mapped the locus on rat chromosome 9 using microsatellite markers and confirmed that the DEK phenotype is independent of the pet genotype (data not shown).…”

“…All rats were housed in conventional conditions under a 14 : 10 h light : dark cycle with ad libitum access to water and standard chow (CR-LPF, Oriental Yeast Co. Ltd., Tokyo, Japan). Room temperature and humidity were maintained at 20 ± 2°C and 50 ± 10%, respectively [14, 15]. Their body weight was measured weekly, with nonfasting blood glucose levels measured between 1 and 7 pm at the ages of 5, 10, 15, 22, and 30 weeks.…”

“…Tissue samples collected from euthanatized rats aged 15 and 30 weeks were weighed with an analytical balance then fixed in neutral buffered 10% formalin solution or 4% paraformaldehyde in phosphate-buffered saline (PBS). The samples were rinsed with PBS, dehydrated, and embedded in paraffin following standard procedures [14, 15]. Samples were then sectioned 4 μ m thick for hematoxylin and eosin (H&E), periodic acid-Schiff (PAS), and Masson's trichrome staining and immunofluorescence.…”