Pre-B-cell transcription factor 1 and steroidogenic factor 1 synergistically regulate adrenocortical growth and steroidogenesis.
A variety of transcription factors including Wilms tumor gene (Wt-1), steroidogenic factor 1 (Sf-1), dosage-sensitive sex reversal, adrenal hypoplasia congenita on the X-chromosome, Gene 1 (Dax-1), and pre-B-cell transcription factor 1 (Pbx1) have been defined as necessary for regular adrenocortical development. However, the role of Pbx1 for adrenal growth and function in the adult organism together with the molecular relationship between Pbx1 and these other transcription factors have not been characterized. We demonstrate that Pbx haploinsufficiency (Pbx1(+/-)) in mice is accompanied by a significant lower adrenal weight in adult animals compared with wild-type controls. Accordingly, baseline proliferating cell nuclear antigen levels are lower in Pbx1(+/-) mice, and unilateral adrenalectomy results in impaired contralateral compensatory adrenal growth, indicating a lower proliferative potential in the context of Pbx1 haploinsufficiency. In accordance with the key role of IGFs in adrenocortical proliferation and development, real-time RT-PCR demonstrates significant lower expression levels of the IGF-I receptor, and up-regulation of IGF binding protein-2. Functionally, Pbx1(+/-) mice display a blunted corticosterone response after ACTH stimulation coincident with lower adrenal expression of the ACTH receptor (melanocortin 2 receptor, Mc2-r). Mechanistically, in vitro studies reveal that Pbx1 and Sf-1 synergistically stimulates Mc2-r promoter activity. Moreover, Sf-1 directly activates the Pbx1 promoter activity in vitro and in vivo. Taken together, these studies provide evidence for a role of Pbx1 in the maintenance of a functional adrenal cortex mediated by synergistic actions of Pbx1 and Sf-1 in the transcriptional regulation of the critical effector of adrenocortical differentiation, the ACTH receptor.
Lichtenauer
Urs D
UD
Division of Endocrine Research, Department of Medicine Innenstadt, University Hospital Munich, Ziemssenstrasse 1, D-80336 Munich, Germany.
Duchniewicz
Marlena
M
Kolanczyk
Mateusz
M
Hoeflich
Andreas
A
Hahner
Stephanie
S
Else
Tobias
T
Bicknell
Andrew B
AB
Zemojtel
Tomasz
T
Stallings
Nancy R
NR
Schulte
Dominik M
DM
Kamps
Mark P
MP
Hammer
Gary D
GD
Scheele
Jürgen S
JS
Beuschlein
Felix
F
D000302:Adrenal Cortex / Q000187:drug effects / Q000254:growth & development* / Q000473:pathology; D000306:Adrenal Cortex Neoplasms / Q000378:metabolism / Q000473:pathology; D000311:Adrenal Glands / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003345:Corticosterone / Q000378:metabolism; D004357:Drug Synergism; D015870:Gene Expression; D006239:Haplotypes; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006984:Hypertrophy; D051379:Mice; D008822:Mice, Transgenic; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011401:Promoter Regions, Genetic; D018043:Receptors, Corticotropin / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013002:Somatomedins / Q000378:metabolism; D054339:Steroidogenic Factor 1; D013256:Steroids / Q000096:biosynthesis*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D018398:Homeodomain Proteins; C481797:Pbx1 protein, mouse; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D018043:Receptors, Corticotropin; D018160:Receptors, Cytoplasmic and Nuclear; D013002:Somatomedins; D054339:Steroidogenic Factor 1; D013256:Steroids; D014157:Transcription Factors; C515058:steroidogenic factor 1, mouse; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone