Dr Paul Le Tissier

Personal profile

• 2014 - present: Lecturer, University of Edinburgh
• 2013 - 2014: Senior Scientist, University of Manchester
• 2003 - 2011: Career Track Appointment, NIMR, London
• 1993 - 2003 Post-doctoral Researcher, NIMR, London
• 1990 - 1993: Post-doctoral Reseracher, University of Sydney
• 1986 - 1990: PhD, Reading University

Research Theme

• Genes and Development
• Signalling, Homeostasis and Energy Balance  

The anterior pituitary gland is an important regulator of many physiological processes, controlling growth, reproduction, lactation, metabolism and stress.

In different physiological states (puberty, pregnancy, lactation, etc) both the amount and pattern of hormone output change and a combination of these determines how target organ function is modified in response to hormone stimulation.

I use an integrated approach, from the level of individual cells and their organisation to their secretory activity and its effect on whole animal physiology.

Currently my research focuses on three main areas:

Plasticity and Organisation

Output of the anterior pituitary gland is principally regulated by factors released from the hypothalamus and delivered to the gland by the hypophyseal portal veins.

The response of the pituitary will depend on delivery of hypothalamic factors from the capillary circulation, the combined population response of specialised cells and the removal of hormone through the capillary circulation draining from the gland.

In collaboration with Dr Patrice Mollard (Montpellier), we have demonstrated that prolactin and growth hormone cells are organised into networks within the pituitary gland and that their relationship to the vasculature is an important factor affecting the pattern of secretion (Figure 1).

The pattern of organisation is modified by physiological status and affects their secretory activity through coordinated calcium signalling in response to stimulation.

More recently, we have shown emergent experience-dependent adaptive responses in the pituitary, with modification of the prolactin network organisation in response to physiological demand persisting after cessation of challenge.

This leads to improved population activity and hormone secretion following repeat stimulation, even when there is a lag time of several months between sequential demands, a phenomenon similar to long-term potentiation in the brain.

Our ongoing work is determining the functional role of this organisation using transgenic models with opto-genetic tools to test in vivo the propagation of stimulation through the networks of cells and comparing it to stimulation through the portal circulation, again using opto-genetic tools to control release of hypothalamic factors.

We are also studying how network organisation is maintained and modified whilst there is constant turnover of pituitary cells.

We are using transgenic models to study repopulation after inducible ablation of specific populations of cells, as well as how naïve cells, arising from differentiation of pituitary stem cells, are functionally integrated into the network.

These studies will have far-reaching consequences for many other biological systems as the pituitary gland has a central role in physiology (e.g. cardiac and metabolic function).

Features of the adaptive response of the pituitary gland to challenge are likely to be common to other endocrine systems and our studies may provide models for how other less tractable systems function.

Image gallery

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Monitoring secretion

Previous studies of pituitary hormone secretion have focused on single vesicle and single cell monitoring of exocytosis or in vitro perfused tissue and in vivo blood sampling with off-line radioimmunoassay.

Since cell organisation is an important factor in pituitary gland function and the pattern of output is dynamic, new tools are required to allow real-time monitoring of secretion from either intact tissue or in the whole animal.

We have developed a system using a modified upright microscope with an epifluorescent attachment to monitor the output of fluorescent proteins targeted to secretory granules; for example in transgenic mice with fluorescent proteins targeted to prolactin or growth hormone granules.

The secreted fluorophore mimics hormone output and can be monitored several times per second, revealing the dynamics of output with a higher resolution than can be achieved with off-line assay of hormone (Figure 2).

Current studies are focusing on extending this approach to test whether secretion in transgenic mice can be detected in vivo with fibre optic cables using modified forms of the secreted Gaussia luciferase, which would allow sensitive luminescent detection of secretion.

An alternative approach is to monitor receptor activation using split-luciferases which only become active with ligand binding, allowing us to monitor exposure of different tissues to hormone.

We are also currently investigating whether electrical biosensors could be used to measure hormones by fast-scan cyclic voltammetry, impedence spectroscopy and surface Plasmon resonance.

These sensors could, in principle, be implanted within a conscious, freely moving mouse and extend studies of pulsatile secretion to this species, as well as have potential for clinical applications in the measurement of dynamic hormone output.

The development of biosensors would be applicable to the studies of peptide secretion in a number of other systems, both in the periphery and within tissue such as the brain.

Pathology

The two principal pathologies associated with the anterior pituitary are hormone deficiency, most frequently found in children and resulting from mutations of genes regulating specialised cell differentiation and function, and hormone excess resulting from tumours, which are mostly benign but lead to conditions such as acromegaly and Cushing’s syndrome.

Previously, in collaboration with Professor Mehul Dattani and Dr Juan Pedro Martinez-Barbera at Great Ormond Street Hospital and the Institute for Child Health my group has studied how mutations in the Pit-1 transcription factor relate to pituitary dysfunction in patients and demonstrated that activation of the Wnt/ß-catenin pathway in pituitary progenitors (but not differentiated cells) leads to craniopharyngioma, a rare but devastating tumour in children.

Recently we have developed a mouse model with inducible expression of constitutively active Gsalpha which develop pituitary growth hormone tumours, similar to those found in humans with a somatic mutation activating the same protein.

We are using this model to investigate the processes leading to tumour formation, as well as the efficacy of different therapeutic compounds.

We have also shown that we can transduce pituitary cells in vivo with lentiviral constructs and will use this to model tumour generation with a focal expansion, recreating the situation in tumour development as well as avoiding homeostatic regulation.

The models developed in these studies will lead to further understanding of the aetiology of pituitary dysfunction and allow the identification and testing of novel therapies.

Funding

• Biotechnology and Biological Sciences Research Council

Collaborations

• Ulrich Boehm, Hamburg, Germany: Use of optogenetics to study hypothalamic and pituitary function; Development of knock-in Cre models
• Helen Christian, Oxford, UK: Studies of pituitary function at EM resolution
• Mehul Dattani, London, UK: Studies of mutations leading to altered pituitary function in humans
• Jacques Drouin, Montreal, Canada: Microarray analysis of gene expression in different pituitary cell types
• Dave Grattan, Dunedin, New Zealand: Development of tools for measurement of pulsatile hormone secretion in mice; generation and use of mouse with floxed PRLR
• Kagan Kerman, Toronto, Canada: Development of electrochemical biosensors of pituitary hormones
• Andy Levy, Bristol, UK: Control of pituitary cell populations and foetal programming of the GH axis
• Juan Pedro Martinez-Barbera, London, UK: Consequence of altered signalling in adult and embryonic pituitary
• Cynthia Andoniadou, London, UK: Stem cells and the control of pituitary regeneration
• Patrice Mollard, Montpellier, France: Organisation and function of cells in the pituitary and hypothalamus
• Marta Korbonits, London, UK: Modelling the role of the gsp oncogene in pituitary tumours in humans

• Mike White, Manchester, UK: Use of luciferase based tools for monitoring pituitary function.

• Takeaki Ozawa, Tokyo, Japan: development of split luciferase sensors of endocrine cell signalling and function.

Selected publications

Le Tissier P, Campos P, Lafont C, Romanò N, Hodson DJ, Mollard P. An updated view of hypothalamic-vascular-pituitary unit function and plasticity. Nat Rev Endocrinol. 2016 Dec 9. doi: 10.1038/nrendo.2016.193. [Epub ahead of print] Review. PubMed PMID: 27934864.

Gregory LC, Alatzoglou KS, McCabe MJ, Hindmarsh PC, Saldanha JW, Romano N, Le Tissier P, Dattani MT. Partial Loss of Function of the GHRH Receptor Leads to Mild Growth Hormone Deficiency. J Clin Endocrinol Metab. 2016 Oct;101(10):3608-3615. PubMed PMID: 27501283.

Brown RS, Kokay IC, Phillipps HR, Yip SH, Gustafson P, Wyatt A, Larsen CM, Knowles P, Ladyman SR, LeTissier P, Grattan DR. (2016). Conditional Deletion of the Prolactin Receptor Reveals Functional Subpopulations of Dopamine Neurons in the Arcuate Nucleus of the Hypothalamus. J Neurosci. 236(35):9173-85. PMID: 27581458.

Le Tissier PR, Hodson DJ, Martin AO, Romanò N, Mollard P.(2015) Plasticity of the prolactin (PRL) axis: mechanisms underlying regulation of output in female mice. Adv Exp Med Biol. 846:139-62

Alatzoglou KS, Alice Webb E, Le Tissier P, Dattani MT. (2014) Isolated growth hormone deficiency (ghd) in childhood and adolescence: recent advances. Endocr Rev. 2014 Jan 22:er20131067. [Epub ahead of print]

Andoniadou, CL, Matsushima, D, Mousavy-Gharavy, N, Signore, M, Mackintosh, AI, Gaston-Massuet, C, Jacques, T, Le Tissier, P, Dattani, MT, Pevny, LH, Martinez-Barbera, JP (2013) The Sox2+ population of the adult murine pituitary includes stem cells with tumour-inducing potential. Cell Stem Cell, 13, 433-435.

Romano, N., Yip, S., Hodson, D., Duvoid-Guillou, A., Parnaudeau, S., Kirk, S., Tronche, F., Bonnefont, X., Le Tissier, P., Bunn, S., Grattan, D., Mollard, P., Martin, A. (2013) Plasticity of hypothalamic dopamine neurons during lactation results in dissociation of electrical activity and release. Journal of Neuroscience, 33, 4424-4433.

Cheung, L., Rizzoti, K., Lovell-Badge, R. & Le Tissier, P. (2013) Pituitary phenotypes of mice lacking the Notch signalling ligand Delta-like 1 homologue (Dlk1). Journal of Neuroendocrinology, 25, 391-401.

Li, Q., Li, N., Le Tissier, P., Grattan, D.R. & Kerman, K. (2012) Miniaturized Electrochemical Immunosensor for Label-Free Detection of Growth Hormone. Electroanalysis, 24, 1272-1276.

Sun, Y., Bak, B., Schoenmakers, N., van Trotsenburg, A.S., Oostdijk, W., Voshol, P., Cambridge, E., White, J.K., Le Tissier, P., Gharavy, S.N., Martinez-Barbera, J.P., Stokvis-Brantsma, W.H., Vulsma, T., Kempers, M.J., Persani, L., Campi, I., Bonomi, M., Beck-Peccoz, P., Zhu, H., Davis, T.M., Hokken-Koelega, A.C., Del Blanco, D.G., Rangasami, J.J., Ruivenkamp, C.A., Laros, J.F., Kriek, M., Kant, S.G., Bosch, C.A., Biermasz, N.R., Appelman-Dijkstra, N.M., Corssmit, E.P., Hovens, G.C., Pereira, A.M., den Dunnen, J.T., Wade, M.G., Breuning, M.H., Hennekam, R.C., Chatterjee, K., Dattani, M.T., Wit, J.M. & Bernard, D.J. (2012) Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement. Nature Genetics, 44, 1375-1381.

Le Tissier, P.R., Hodson, D.J., Lafont, C., Fontanaud, P., Schaeffer, M. & Mollard, P. (2012) Anterior pituitary cell networks. Frontiers in Neuroendocrinology, 33, 252-266.

Jayakody, S.A., Andoniadou, C.L., Gaston-Massuet, C., Signore, M., Cariboni, A., Bouloux, P.M., Le Tissier, P., Pevny, L.H., Dattani, M.T. & Martinez-Barbera, J.P. (2012) SOX2 regulates the hypothalamic-pituitary axis at multiple levels. Journal of Clinical Investigation, 122, 3635-3646.

Andoniadou, C.L., Gaston-Massuet, C., Reddy, R., Schneider, R.P., Blasco, M.A., Le Tissier, P., Jacques, T.S., Pevny, L.H., Dattani, M.T. & Martinez-Barbera, J.P. (2012) Identification of novel pathways involved in the pathogenesis of human adamantinomatous craniopharyngioma. Acta Neuropathology, 124, 259-271.

Hodson, D.J., Schaeffer, M., Romano, N., Fontanaud, P., Lafont, C., Birkenstock, J., Molino, F., Christian, H., Lockey, J., Carmignac, D., Fernandez-Fuente, M., Le Tissier, P. & Mollard, P. (2012) Existence of long-lasting experience-dependent plasticity in endocrine cell networks. Nature Communications, 3, 605.

Turton, J.P., Strom, M., Langham, S., Dattani, M.T. & Le Tissier, P. (2012) Two novel mutations in the POU1F1 gene generate null alleles through different mechanisms leading to combined pituitary hormone deficiency. Clinical Endocrinology, 76, 387-393.

Schaeffer, M., Hodson, D.J., Meunier, A.C., Lafont, C., Birkenstock, J., Carmignac, D., Murray, J.F., Gavois, E., Robinson, I.C., Le Tissier, P. & Mollard, P. (2011) Influence of estrogens on GH-cell network dynamics in females: a live in situ imaging approach. Endocrinology, 152, 4789-4799.

Gaston-Massuet, C., Andoniadou, C.L., Signore, M., Jayakody, S.A., Charolidi, N., Kyeyune, R., Vernay, B., Jacques, T.S., Taketo, M.M., Le Tissier, P., Dattani, M.T. & Martinez-Barbera, J.P. (2011) Increased Wingless (Wnt) signaling in pituitary progenitor/stem cells gives rise to pituitary tumors in mice and humans. Proceedings of the National Academy of Science U S A, 108, 11482-11487.

Stuckey, D.W., Clements, M., Di-Gregorio, A., Senner, C.E., Le Tissier, P., Srinivas, S. & Rodriguez, T.A. (2011) Coordination of cell proliferation and anterior-posterior axis establishment in the mouse embryo. Development, 138, 1521-1530.

Guillou, A., Romano, N., Bonnefont, X., Le Tissier, P., Mollard, P. & Martin, A.O. (2011) Modulation of the tyrosine kinase receptor Ret/glial cell-derived neurotrophic factor (GDNF) signaling: a new player in reproduction induced anterior pituitary plasticity? Endocrinology, 152, 515-525.

He, Z., Fernandez-Fuente, M., Strom, M., Cheung, L., Robinson, I.C. & Le Tissier, P. (2011) Continuous on-line monitoring of secretion from rodent pituitary endocrine cells using fluorescent protein surrogate markers. Journal of Neuroendocrinology, 23, 197-207.

Sanchez-Cardenas, C., Fontanaud, P., He, Z., Lafont, C., Meunier, A.C., Schaeffer, M., Carmignac, D., Molino, F., Coutry, N., Bonnefont, X., Gouty-Colomer, L.A., Gavois, E., Hodson, D.J., Le Tissier, P., Robinson, I.C. & Mollard, P. (2010) Pituitary growth hormone network responses are sexually dimorphic and regulated by gonadal steroids in adulthood. Proceedings of the National Academy of Science U S A, 107, 21878-21883.

Lafont, C., Desarmenien, M.G., Cassou, M., Molino, F., Lecoq, J., Hodson, D., Lacampagne, A., Mennessier, G., El Yandouzi, T., Carmignac, D., Fontanaud, P., Christian, H., Coutry, N., Fernandez-Fuente, M., Charpak, S., Le Tissier, P., Robinson, I.C. & Mollard, P. (2010) Cellular in vivo imaging reveals coordinated regulation of pituitary microcirculation and GH cell network function. Proceedings of the National Academy of Science U S A, 107, 4465-4470.

Castrique, E., Fernandez-Fuente, M., Le Tissier, P., Herman, A. & Levy, A. (2010) Use of a prolactin-Cre/ROSA-YFP transgenic mouse provides no evidence for lactotroph transdifferentiation after weaning, or increase in lactotroph/somatotroph proportion in lactation. Journal of Endocrinology, 205, 49-60.

Waite, E., Lafont, C., Carmignac, D., Chauvet, N., Coutry, N., Christian, H., Robinson, I., Mollard, P. & Le Tissier, P. (2010) Different degrees of somatotroph ablation compromise pituitary growth hormone cell network structure and other pituitary endocrine cell types. Endocrinology, 151, 234-243.

Chauvet, N., El-Yandouzi, T., Mathieu, M.N., Schlernitzauer, A., Galibert, E., Lafont, C., Le Tissier, P., Robinson, I.C., Mollard, P. & Coutry, N. (2009) Characterization of adherens junction protein expression and localization in pituitary cell networks. Journal of Endocrinology, 202, 375-387.

Le Tissier, P.R., Carmignac, D.F., Lilley, S., Sesay, A.K., Phelps, C.J., Houston, P., Mathers, K., Magoulas, C., Ogden, D. & Robinson, I.C. (2005) Hypothalamic growth hormone-releasing hormone (GHRH) deficiency: targeted ablation of GHRH neurons in mice using a viral ion channel transgene. Molecular Endocrinology, 19, 1251-1262.

Stevens, A., Bock, M., Ellis, S., Le Tissier, P., Bishop, K.N., Yap, M.W., Taylor, W. & Stoye, J.P. (2004) Retroviral capsid determinants of Fv1 NB and NR tropism. Journal of Virology, 78, 9592-9598.

Bains, R.K., Wells, S.E., Flavell, D.M., Fairhall, K.M., Strom, M., Le Tissier, P. & Robinson, I.C. (2004) Visceral obesity without insulin resistance in late-onset obesity rats. Endocrinology, 145, 2666-2679.

De Jersey, J., Carmignac, D., Le Tissier, P., Barthlott, T., Robinson, I. & Stockinger, B. (2004) Factors affecting the susceptibility of the mouse pituitary gland to CD8 T-cell-mediated autoimmunity. Immunology, 111, 254-261.

Lilley, S., LeTissier, P. & Robbins, J. (2004) The discovery and characterization of a proton-gated sodium current in rat retinal ganglion cells. Journal of Neuroscience, 24, 1013-1022.

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