Prolactin cells: A model for the control of post-embryonic cell proliferation and differentiation

Lead Research Organisation: MRC National Inst for Medical Research

Abstract

The numbers of some types of cell in a human or other animal are constantly changing, depending on the bodys requirements. Whilst it is important to produce enough cells for correct function, excess proliferation could lead to inappropriate function or even tumour formation. Researchers at the National Institute for Medical Research are studying how cell numbers are controlled using cells producing prolactin, which is a hormone principally involved in pregnancy and production of milk. The number of cells producing prolactin can change dramatically in some situations and whilst some of the mechanisms controlling this are known many have yet to be identified. By marking prolactin cells with fluorescent proteins, the researchers can observe how prolactin cells develop in rodents. They also use rodents with naturally occurring and artificially created changes in their genetic control of prolactin cell proliferation, allowing them to find new mechanisms that determine the number of these cells. The researchers are collaborating with Great Ormond Street Hospital to investigate whether patients referred from all over the UK have genetic differences in their control of prolactin cell number that are similar to those found in rodents.

Technical Summary

We are interested in the mechanisms which control cells which are capable of proliferating and changing to fulfil many different roles, poorly understood processes in the post-embryonic development of a number of biological systems. Alterations in cellular proliferation and differentiation can lead to the failure of many biological processes as well as the development of tumours. Lactotrophs, our model system, produce prolactin in the anterior pituitary of mammals. They are derived from precursor cells, which can also differentiate into somatotrophs, the cells that produce growth hormone, and there is a close relationship between the development of the two cell types. Lactotroph cell numbers alter dramatically throughout an animals life, depending on physiological status, increasing three-fold during pregnancy and lactation but returning to pre-pregnancy numbers within a short time after weaning. Our aim is to understand the mechanisms and factors regulating with lactotroph population. Dwarf (dw/dw) rats have a reduction in somatrophs and an abnormally high number of lactotrophs. Ongoing studies in our laboratory are focused on identifying the gene responsible for the dwarf phenotype by positional cloning. Dr Mehul Dattani (Institute of Child Health, London) has a number of patients with a similar pituitary hormone profile to that seen in dw rats, we will collaborate with Dr Dattani to test whether mutations in a human monologue of dw occur and produce a similar phenotype in human subjects. We have generated transgenic animals in which red fluorescent protein, under the control of a rat prolactin promoter, is produced in lactotroph cells. By crossing these with existing transgenic mice with somatotrophs labelled with green fluorescent protein, we will generate doubly transgenic mice in which lactotroph, somatotroph and mammosomatroph (an intermediate cell type) populations are readily identified and quantified. In collaboration with Dr Andy Levy (URCN, Bristol) we will use these mice to assess the mitotic, transdifferential and apoptotic activity of lactotroph cells before, during and after pregnancy, lactation and weaning. In collaboration with Dr Patrice Mollard (INSERM, Montpellier) we will analyse the organisation of lactotroph cells in the pituitaries of these mice using the two-photon imaging technique. This will allow us to define whether lactotrophs are organised in a 3-D network similar to that found for other pituitary cell types and how this alters during functionally altered states. The populations of neurons in the hypothalamus controlling pituitary function are also plastic and that number alters depending on feedback regulation by their target pituitary hormones. Whether this occurs through altered neuronal activation, silencing or survival is unclear. We are generating transgenic mice expressing Cre recombinase in specific populations of neurons in the hypothalamus of the ROSA-26 reporter strain. This will allow us to identify different populations of the hypothalamic neurons controlling lactotrophs and image the effects of different feedback regulation.

Publications

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Description Characterisation of cell network organisation and function in the pituitary 
Organisation University of Bristol
Department School of Clinical Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Generation and characterisation of transgenic mice expressing fluorescent proteins in growth hormone and prolactin cells, as well as transgenic mice with altered pituitary function.
Collaborator Contribution Elucidated the relationship between prolactin and growth hormone cells of the pituitary
Impact PMID: 19505949 PMID: 19887571 PMID: 20160103
 
Description Characterisation of cell network organisation and function in the pituitary 
Organisation University of Regensburg
Department Institute of Functional Genomics
Country Germany 
Sector Academic/University 
PI Contribution Generation and characterisation of transgenic mice expressing fluorescent proteins in growth hormone and prolactin cells, as well as transgenic mice with altered pituitary function.
Collaborator Contribution Elucidated the relationship between prolactin and growth hormone cells of the pituitary
Impact PMID: 19505949 PMID: 19887571 PMID: 20160103
 
Description Relationship and population dynamics of different cell types in the pituitary 
Organisation University of Bristol
Department School of Clinical Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Generated and used transgenic mouse models
Collaborator Contribution We generated the transgenic mouse models. The collaborator characterised these.
Impact Publication PMID: 20139144
Start Year 2006