PKA signaling drives reticularis differentiation and sexually dimorphic adrenal cortex renewal

JCI Insight. 2018 Jan 25;3(2):e98394. doi: 10.1172/jci.insight.98394.


The adrenal cortex undergoes remodeling during fetal and postnatal life. How zona reticularis emerges in the postnatal gland to support adrenarche, a process whereby higher primates increase prepubertal androgen secretion, is unknown. Using cell-fate mapping and gene deletion studies in mice, we show that activation of PKA has no effect on the fetal cortex, while it accelerates regeneration of the adult cortex, triggers zona fasciculata differentiation that is subsequently converted into a functional reticularis-like zone, and drives hypersecretion syndromes. Remarkably, PKA effects are influenced by sex. Indeed, testicular androgens increase WNT signaling that antagonizes PKA, leading to slower adrenocortical cell turnover and delayed phenotype whereas gonadectomy sensitizes males to hypercorticism and reticularis-like formation. Thus, reticularis results from ultimate centripetal conversion of adult cortex under the combined effects of PKA and cell turnover that dictate organ size. We show that PKA-induced progenitor recruitment is sexually dimorphic and may provide a paradigm for overrepresentation of women in adrenal diseases.

Keywords: Development; Endocrinology; Genetic diseases; Mouse models; Protein kinases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenarche / metabolism
  • Age Factors
  • Androgens / metabolism
  • Animals
  • Cell Differentiation / physiology
  • Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / genetics
  • Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / metabolism*
  • Embryo, Mammalian
  • Female
  • Male
  • Mice
  • Mice, Knockout
  • Models, Animal
  • Sex Characteristics*
  • Signal Transduction / physiology*
  • Zona Fasciculata / metabolism*
  • Zona Reticularis / metabolism*


  • Androgens
  • Cyclic AMP-Dependent Protein Kinase RIalpha Subunit
  • Prkar1a protein, mouse