Figure 2. Reciprocal signaling between the capsule and cortex coordinately regulates SHH and Wnt pathway activation.

Schematic representation of the crosstalk between the mesenchymal capsule and underlying adrenal cortex that is required for SHH and Wnt activity. (Top) Adrenocortical cells in the glomerulosa produce SHH ligands, while capsular cells express the central components of the SHH signaling response, PTCH1 and SMO. In the absence of ligand, PTCH1 inhibits the activity of SMO. SHH ligand binding inactivates PTCH1 and subsequently derepresses SMO, which leads to intracellular signal transduction and the activation of GLI transcription factors. Additionally, PTCH1 and SMO are respectively dependent upon the transmembrane flux of sodium ions and cholesterol availability. (Bottom) Capsular-to-cortical signaling regulates Wnt pathway activation. RSPO3 produced by the capsule helps facilitate degradation of ZNRF3 in underlying adrenal cortex. ZNRF3 is a transmembrane E3 ubiquitin ligase that acts to promote the turnover of Wnt receptor complexes. Thus, RSPO3-mediated degradation of ZNRF3 potentiates Wnt pathway activation by increasing the availability of Wnt receptors on the cell surface. Schematic created with BioRender.com.