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Hypothalamic 3',5'-Cyclic Adenosine Monophosphate Response Element-Binding Protein Loss Causes Anterior Pituitary Hypoplasia and Dwarfism in Mice

Molecular Biology of the Cell I (T.M., S.R., O.K., S.C.B., D.C., G.S.), Department of Cellular and Molecular Pathology (H.J.G), Deutsches Krebsforschungszentrum, 69120 Heidelberg, Germany; Institute of Anatomy and Cell Biology, University of Freiburg (O.K.), 79104, Freiburg, Germany; and Peter MacCallum Cancer Centre (T.M., J.M., S.D., R.G.R), East Melbourne 3002, Australia

Address all correspondence and requests for reprints to: Theo Mantamadiotis, Peter MacCallum Cancer Centre, Locked Bag 1, A’Beckett Street, 8006 Victoria, Australia. E-mail: theo.mantamadiotis{at}petermac.org.

The principal regulation of body growth is via a cascade of hormone signals emanating from the hypothalamus, by release of GHRH, which then directs the somatotroph cells of the pituitary to release GH into the blood stream. This in turn leads to activation of signal transducer and activator of transcription 5-dependent expression of genes such as IGF-I in hepatocytes, acid labile substance, and serine protease inhibitor 2.1, resulting in body growth. Here, using conditional cAMP response element binding protein (CREB) mutant mice, we show that loss of the CREB transcription factor in the brain, but not the pituitary, results in reduced postnatal growth consistent with dwarfism caused by GH deficiency. We demonstrate that although there appears to be no significant impact upon the expression of GHRH mRNA in CREB mutant mice, the amount of GHRH peptide is reduced. These findings show that CREB is required for the efficient production of GHRH in hypothalamus, in addition to its previously reported role in pituitary GH production and somatotroph expansion.

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