| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on April 28, 2006
Accepted on July 11, 2006
Cellular & Molecular Biology Graduate Program, and Department of Internal Medicine, Division of Endocrinology, 5568 MSRBII (615-8914), University of Michigan, Ann Arbor, MI
* To whom correspondence should be addressed. E-mail: ghammer{at}umich.edu.
Inhibin knockout (Inh-/-) mice develop gonadal sex-cord tumors and--when gonadectomized--adrenocortical tumors. Previous reports demonstrated that adrenocortical tumors from Inh-/- mice produce estrogen and depend on gonadotropin signaling for initiation. Here we show that in addition to producing estrogen, the adrenocortical tumors display a global change in cellular identity, composed of two unique cell types expressing differing arrays of genes normally restricted to theca and granulosa cells of the ovary. Many of these genes are also induced in wild-type adrenals after gonadectomy or upon chronic gonadotropin stimulation, suggesting that the adrenal cortex normally contains a population of pluripotent cells that can be driven toward an adrenal or gonadal identity given the appropriate pituitary stimuli. A central feature of this altered cellular identity is the switch from predominant expression of Gata6 (endogenous to the adrenal cortex) to Gata4, which defines cellular identity in the ovary. We show that stable transfection of Gata4 in cultured adrenocortical cells is sufficient to activate ovarian-specific genes of both theca and granulose lineages. Spatial analysis of Gata4 expression reveals a distinct pattern of localization to the supcapsular region of the adrenal, which contains undifferentiated progenitor cells that continuously populate the adrenocortical zones. While both wild-type and Inh-/- mice display this pattern, only Inh-/- mice produce tumors composed of these Gata4-positive cells. These data suggest that Inh-/- adrenocortical tumors cells are derived from pluripotent adrenocortical progenitor cells that adopt a gonadal fate due to the convergent loss of inhibin and chronic exposure to elevated gonadotropins.
This article has been cited by other articles:
 |
|
 |
|
  S. Bernichtein, E. Petretto, S. Jamieson, A. Goel, T. J. Aitman, J. M. Mangion, and I. T. Huhtaniemi Adrenal Gland Tumorigenesis after Gonadectomy in Mice Is a Complex Genetic Trait Driven by Epistatic Loci Endocrinology, February 1, 2008; 149(2): 651 - 661. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Doghman, T. Karpova, G. A. Rodrigues, M. Arhatte, J. De Moura, L. R. Cavalli, V. Virolle, P. Barbry, G. P. Zambetti, B. C. Figueiredo, et al. Increased Steroidogenic Factor-1 Dosage Triggers Adrenocortical Cell Proliferation and Cancer Mol. Endocrinol., December 1, 2007; 21(12): 2968 - 2987. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. D. Looyenga and G. D. Hammer Genetic Removal of Smad3 from Inhibin-Null Mice Attenuates Tumor Progression by Uncoupling Extracellular Mitogenic Signals from the Cell Cycle Machinery Mol. Endocrinol., October 1, 2007; 21(10): 2440 - 2457. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Hershkovitz, F. Beuschlein, S. Klammer, M. Krup, and Y. Weinstein Adrenal 20{alpha}-Hydroxysteroid Dehydrogenase in the Mouse Catabolizes Progesterone and 11-Deoxycorticosterone and Is Restricted to the X-Zone Endocrinology, March 1, 2007; 148(3): 976 - 988. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
