Leiden University Scholarly Publications

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Laan, S. van der (2008)

Expression and function of nuclear receptor coregulators in brain: understanding the cell-specific effects of glucocorticoids

Doctoral Thesis
Currently, the raising awareness of the role of glucocorticoids in the onset of numerous (neuro)-pathologies constitutes the increasing necessity of understanding the mechanisms of action of glucocorticoids in bodily processes and brain functioning. Glucocorticoids mediate their effects by binding to intracellular receptors which act as transcription factors. A remarkable and yet unexplained phenomenon described more than two decades ago, is the cell-specific effects glucocorticoids bring about on gene expression in brain. For example, while glucocorticoids suppress corticotrophin-releasing hormone (CRH) synthesis in the hypothalamus, production of CRH in the central nucleus of the amygdala (CeA) is stimulated by increased hormone levels. Inasmuch as the neuroanatomical distribution of the corticosteroid receptors does not satisfactorily explain these effects, it is of interest to decipher the role of recently discovered coregu lator proteins that modulate the direction and the...Show moreCurrently, the raising awareness of the role of glucocorticoids in the onset of numerous (neuro)-pathologies constitutes the increasing necessity of understanding the mechanisms of action of glucocorticoids in bodily processes and brain functioning. Glucocorticoids mediate their effects by binding to intracellular receptors which act as transcription factors. A remarkable and yet unexplained phenomenon described more than two decades ago, is the cell-specific effects glucocorticoids bring about on gene expression in brain. For example, while glucocorticoids suppress corticotrophin-releasing hormone (CRH) synthesis in the hypothalamus, production of CRH in the central nucleus of the amygdala (CeA) is stimulated by increased hormone levels. Inasmuch as the neuroanatomical distribution of the corticosteroid receptors does not satisfactorily explain these effects, it is of interest to decipher the role of recently discovered coregu lator proteins that modulate the direction and the magnitude of steroid receptor-driven transcription. Therefore, in the current thesis the expression and function of central coregulators was studied: the coactivators SRC1a and SRC1e along with the corepressors N-CoR and SMRT were found to be expressed in brain and involved in regulation of CRH gene expression. Finally, a method that allows detection of coregulator recruitment by steroid receptors in brain tissue was developed.Show less
Brain
CRH
Glucocorticoids
GR
MR
N-CoR
PVN
SMRT
SRC1
Stress
All authors
Laan, S. van der
Supervisor
Kloet, E.R. de
Co-supervisor
Meijer, O.C.
Committee
Kalkhoven, E.; Dijke, P. ten; Noteborn, M.H.M.; Schaaf, M.J.; Löwik, C.W.G.M.; Berkel, T.J.C. van; Danhof, M.
Qualification
Doctor (dr.)
Awarding Institution
Leiden/Amsterdam Center for Drug Research (LACDR), Faculty of Science, Leiden University
Date
2008-11-06
ISBN (print)
9789064642944

Juridical information

Court
LEI Universiteit Leiden