Evidence of Adrenal Failure in Aging Dax1-Deficient Mice

Abstract

Dosage-sensitive sex reversal, adrenal hypoplasia congenita (AHC) critical region on the X chromosome, gene 1 (Dax1) is an orphan nuclear receptor essential for development and function of the mammalian adrenal cortex and gonads. DAX1 was cloned as the gene responsible for X-linked AHC, which is characterized by adrenocortical failure necessitating glucocorticoid replacement. Contrary to these human data, young mice with genetic Dax1 knockout (Dax1(-/Y)) exhibit adrenocortical hyperfunction, consistent with the historic description of Dax1 as a transcriptional repressor that inhibits steroidogenic factor 1-dependent steroidogenesis. This paradox of molecular function and two apparently opposite phenotypes associated with Dax1 deficiency in mice and humans is compounded by the recent observations that under certain circumstances, Dax1 can serve as a transcriptional activator of steroidogenic factor 1. The recently revealed role of Dax1 in embryonic stem cell pluripotency, together with the observation that its expression in the adult adrenal is restricted to the subcapsular cortex, where presumptive undifferentiated progenitor cells reside, has led us to reexamine the phenotype of Dax1(-/Y) mice in order to reconcile the conflicting mouse and human data. In this report, we demonstrate that although young Dax1(-/Y) mice have enhanced steroidogenesis and subcapsular adrenocortical proliferation, as these mice age, they exhibit declining adrenal growth, decreasing adrenal steroidogenic capacity, and a reversal of their initial enhanced hormonal sensitivity. Together with a marked adrenal dysplasia in aging mice, these data reveal that both Dax1(-/Y) mice and patients with X-linked AHC exhibit adrenal failure that is consistent with adrenocortical subcapsular progenitor cell depletion and argue for a significant role of Dax1 in maintenance of these cells.

Adrenocortical Growth and Cancer

“…As these mice age, they exhibit altered subcapsular proliferation and steroidogenesis, which can be explained by depletion of stem/progenitor cells. These data reveal that both deficient-Dax1 mice and patients with X-linked AHC exhibit adrenal failure that is consistent with adrenocortical subcapsular progenitor cell depletion and argue for a significant role of Dax1 in maintenance of these cells (285).…”

MANAGEMENT OF ENDOCRINE DISEASE: Regenerative therapies in autoimmune Addison’s disease

“…Hence, as DAX1 is only present in the subcapsular adrenal cells, steroidogenesis is inhibited in these undifferentiated progenitor cells and the 'stemness' of ACSCs is maintained. Interestingly, young DAX1-knockout mice initially exhibited a hyperfunction adrenal state consistent with the loss of DAX1-dependant inhibition of steroidogenesis (97) but was followed by the attenuation of steroidogenic capacity when they aged, with profound loss of the subcapsular region, and concomitant adrenal dysplasia was observed (97,98). This model is in keeping with a number of patients with DAX1 mutations demonstrating enhancement of steroidogenic function state prior to the development of adrenal failure in later childhood (99,100).…”

A man with a DAX1/NR0B1 mutation, normal puberty, and an intact hypothalamic–pituitary–gonadal axis but deteriorating oligospermia during long-term follow-up

“…The phenotypes of the proband, his brother, and his nephew illustrate the different possible adrenal consequences of identical DAX1 mutations (12,13). The adrenal phenotypes of the proband and his brother are reminiscent of the mouse model, in which adrenal failure is a late event: after a transient period of enhanced adrenal susceptibility to ACTH, aging Dax1 knockout mice display decreased adrenal steroidogenic capacity and adrenal cell proliferation (14). We do not know whether the proband and his brother had a period of elevated adrenal steroid hormone production before adrenal failure.…”