Hypothalamic 3',5'-cyclic adenosine monophosphate response element-binding protein loss causes anterior pituitary hypoplasia and dwarfism in mice.
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.
Mantamadiotis
Theo
T
Molecular Biology of the Cell, Deutsches Krebsforschungszentrum, Heidelberg, Germany. theo.mantamadiotis@petermac.org
Kretz
Oliver
O
Ridder
Stephanie
S
Bleckmann
Susanne C
SC
Bock
Dagmar
D
Gröne
Hermann-Josef
HJ
Malaterre
Jordane
J
Dworkin
Sebastian
S
Ramsay
Robert G
RG
Schütz
Günther
G
D000818:Animals; D001921:Brain / Q000378:metabolism; D003433:Crosses, Genetic; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D004392:Dwarfism / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005298:Fertility / Q000235:genetics; D013006:Growth Hormone / Q000378:metabolism; D013007:Growth Hormone-Releasing Hormone / Q000378:metabolism*; D007031:Hypothalamus / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007774:Lactation / Q000235:genetics; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D010903:Pituitary Gland, Anterior / Q000002:abnormalities* / Q000378:metabolism*; D013004:Somatostatin / Q000378:metabolism
C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D013004:Somatostatin; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone