Plasticity of the prolactin (PRL) axis: mechanisms underlying regulation of output in female mice.

The output of prolactin (PRL) is highly dynamic with dramatic changes in its secretion from the anterior pituitary gland depending on prevailing physiological status. In adult female mice, there are three distinct phases of output and each of these is related to the functions of PRL at specific stages of reproduction. Recent studies of the changes in the regulation of PRL during its period of maximum output, lactation, have shown alterations at both the level of the anterior pituitary and hypothalamus. The PRL-secreting cells of the anterior pituitary are organised into a homotypic network in virgin animals, facilitating coordinated bouts of activity between interconnected PRL cells. During lactation, coordinated activity increases due to the changes in structural connectivity, and this drives large elevations in PRL secretion. Surprisingly, these changes in connectivity are maintained after weaning, despite reversion of PRL output to that of virgin animals, and result in an augmented output of hormone during a second lactation. At the level of the hypothalamus, tuberoinfundibular dopamine (TIDA) neurons, the major inhibitors of PRL secretion, have unexpectedly been shown to remain responsive to PRL during lactation. However, there is an uncoupling between TIDA neuron firing and dopamine secretion, with a potential switch to enkephalin release. Such a process may reinforce hormone secretion through dual disinhibition and stimulation of PRL cell activity. Thus, integration of signalling along the hypothalamo-pituitary axis is responsible for increased secretory output of PRL cells during lactation, as well as allowing the system to anticipate future demands.

Pituitary phenotypes of mice lacking the notch signalling ligand delta-like 1 homologue.

The Notch signalling pathway ligand delta-like 1 homologue (Dlk1, also named Pref1) is expressed throughout the developing pituitary and becomes restricted to mostly growth hormone (GH) cells within the adult gland. We have investigated the role of Dlk1 in pituitary development and function from late embryogenesis to adulthood using a mouse model completely lacking the expression of Dlk1. We confirm that Dlk1-null mice are shorter and weigh less than wild-type littermates from late gestation, at parturition and in adulthood. A loss of Dlk1 leads to significant reduction in GH content throughout life, whereas other pituitary hormones are reduced to varying degrees depending on sex and age. Both the size of the pituitary and the proportion of hormone-producing cell populations are unchanged, suggesting that there is a reduction in hormone content per cell. In vivo challenge of mutant and wild-type littermates with growth hormone-releasing hormone and growth hormone-releasing hexapeptide shows that reduced GH secretion is unlikely to account for the reduced growth of Dlk1 knockout animals. These data suggest that loss of Dlk1 gives rise to minor pituitary defects manifesting as an age- and sex-dependent reduction in pituitary hormone contents. However, Dlk1 expression in other tissue is most likely responsible for the weight and length differences observed in mutant animals.

Anterior pituitary cell networks.

Both endocrine and non-endocrine cells of the pituitary gland are organized into structural and functional networks which are formed during embryonic development but which may be modified throughout life. Structural mapping of the various endocrine cell types has highlighted the existence of distinct network motifs and relationships with the vasculature which may relate to temporal differences in their output. Functional characterization of the network activity of growth hormone and prolactin cells has revealed a role for cell organization in gene regulation, the plasticity of pituitary hormone output and remarkably the ability to memorize altered demand. As such, the description of these endocrine cell networks alters the concept of the pituitary from a gland which simply responds to external regulation to that of an oscillator which may memorize information and constantly adapt its coordinated networks' responses to the flow of hypothalamic inputs.

Endogenous retroviruses and the evolution of resistance to retroviral infection.

The current AIDS epidemic has rekindled interest in the evolution of retroviruses and the development of resistance to infection. Retroviruses and their vertebrate hosts have coexisted for millions of years, during which time a variety of host defence mechanisms has evolved. One repeated strategy is to use endogenous retroviruses to combat infection by their exogenous relatives.

Development of an assay method for purine catabolic enzymes in the mouse and its adaptation for use on an autoanalyzer.

An assay method has been developed for the purine catabolic enzymes adenosylhomocysteinase, adenosine deaminase (ADA), purine-nucleoside phosphorylase (PNP), and urate oxidase in mice. The assay links H2O2 produced during purine catabolism to the production of a dye complex. The assay method has been developed for ADA and PNP in erythrocytes and for all four enzymes in liver. The assay is cheap, sensitive, and easy to perform. The dye complex absorbs in the visible range, negating the need for an expensive ultraviolet spectrophotometer and allowing the use of an autoanalyzer.