Characterisation of phenotypic determinants in rat models of growth retardation

• Main Author: El-Kasti, Muna M
• Format: Dissertation
• Language: English
• Published: Cardiff University 2004

In this thesis, I describe work on the physiological basis of dwarfism in both established (dw/dw) and novel (78N) rat models. In the dwarf (dw/dw) rat, an unknown mutation causes a severe, sub-total growth hormone (GH) deficiency associated with somatotroph hypoplasia, and an increase in lactotroph numbers and prolactin (PRL) storage. It has, recently, been shown that the dw/dw pituitary contains a unique, morphologically distinct lactotroph, the 'intermediate' lactotroph, which has morphological features between those of the type I and II lactotroph subtypes. These 'intermediate' lactotrophs also show functional features of somatotrophic lineage, releasing PRL in response to ghrelin. This female-specific induction of PRL secretion is oestrogen-dependent. The present study reveals that in pregnancy the population of 'intermediate' lactotrophs increases in parallel with the lactotrophic lineage. We have taken two approaches to investigate whether elevated GH releasing factor (GRF) gives rise to the 'intermediate' lactotroph in the dw/dw pituitary. The absence of the 'intermediate' lactotroph in the GRF-insensitive little (lit/lit) mouse, and a possible reduction in 'intermediate' lactotrophs in monosodium glutamate (MSG)-treated dw/dw rats, suggest that the presence of this unique lactotroph subtype in dw/dw pituitary is regulated, in part by GRF. Although small numbers of 'intermediate' lactotrophs are present in pregnant normal female rats, they do not appear to play a significant role. Pregnancy is also associated with an increase in type I lactotrophs, but no change in somatotrophs. The accompanying increase in baseline circulating GH does not elevate plasma insulin like growth factor I (IGF-I) levels, or stimulate skeletal growth, and may be derived from a placental GH-like protein. A novel transgenic rat line---78N---was previously generated in our laboratory. It is a presumed insertional-mutant that exhibits a pleiotropic phenotype associated with neonatal male lethality. Females exhibit juvenile-onset growth retardation. Initial investigation of the cause of the growth retardation showed that the skeletal impairment is GH-independent. In the present study, parallel postmortem examination has revealed kidney abnormalities in both male and female mutants. Morphological analysis showed alteration of the normal cortico-medullary architecture. Molecular analysis of the neonatal male kidney transcriptome revealed numerous differentially expressed genes including kidney androgen-regulated protein (KAP) and neural precursor cells expressed developmentally down-regulated 4 (Nedd4) WW domain binding protein (N4WBP4). The 78N line may be a useful model of idiopathic short stature (ISS) associated with idiopathic nephritic syndrome---minimal change nephropathy (MCD) or disease.