Progenitor Cell Expansion and Organ Size of Mouse Adrenal Is Regulated by Sonic Hedgehog

Abstract

The adrenal capsule is postulated to harbor stem/progenitor cells, the progenies of which contribute to the growth of adrenocortex. We discovered that cells in the adrenal capsule are positive for Ptch1 and Gli1, genes indicative of responsiveness to the stimulation of Hedgehog (Hh) ligands. On the other hand, Sonic hedgehog (Shh), one of the mammalian Hh ligands, is expressed in the adrenocortex underneath the adrenal capsule, possibly acting upon the Hh-Responsive capsule. To investigate the functional significance of Shh in adrenal growth, we ablated Shh in an adrenocortex-specific manner using the Steroidogenic factor 1-Cre mouse. Loss of Shh in the adrenocortex led to reduced proliferation of capsular cells and a 50-75% reduction in adrenocortex thickness and adrenal size. The remaining adrenocortex underwent proper zonation and was able to synthesize steroids, indicating that Shh is dispensable for differentiation of adrenocortex. When these animals reached adulthood, their adrenocortex did not undergo compensatory growth in response to a high level of plasma ACTH, and the size of the adrenal remained significantly smaller than the control adrenal. Using a genetic lineage-tracing model, we further demonstrated that the Hh-responding cells in the adrenal capsule migrated centripetally into the adrenocortex. Our results not only provide the genetic evidence to support that the adrenal capsule contributes to the growth of adrenocortex in both fetal and adult life but also identify a novel role of Shh in this process.

DNA methylation and cerebellar development, the regulation of Notch and Shh pathway

“…The blockade of Shh function in vivo resulted in deficient Bergmann glia differentiation as well as abnormal development of Purkinje neurons (Dahmane & Ruiz i Altaba 1999). Previous studies also showed that Shh could be expressed in many kinds of cells in the brain (Huang et al 2010), including choroid plexus and Purkinje cells, but in our study, the Shh-positive cells in cerebellum were Bergmann glia. This tiny difference needs to be explained with further investigation.…”

The adrenal capsule is a signaling center controlling cell renewal and zonation through Rspo3

“…Previous studies have demonstrated a key role for SHH signaling in the recruitment of capsular Gli1 + cells to the steroidogenic lineage (Ching and Vilain 2009;King et al 2009;Huang et al 2010), and Shh has been suggested to be regulated by canonical β-catenin signaling in the adrenal system (Drelon et al 2015) and several other developmental systems (Iwatsuki et al 2007;Ahn et al 2010). To test whether this pathway is affected in Rspo3 mutants, we carried out qPCR, immunohistochemistry, and in situ hybridization (ISH) analysis on E16.5 tissues.…”

“…Shh in turn signals back to recruit capsular cells to form the adrenal cortex, at least during development. The fact that Shh knockout mice show normal adrenal zonation (Huang et al 2010) while Rspo3 deletion affects ZG identity indicates that Rspo3 must also act through additional, Shh-independent pathways. The dramatic thinning of the entire steroidogenic compartment further supports the model of a ZG-driven adrenal cortex renewal, a concept that has been put forward by Freedman et al (2013).…”

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

“…Additionally, lineage tracing showed that the descendants of the downstream activator of the SHH pathway, GLI1, which is only found in the adrenal capsule, also gave rise to differentiated adrenocortical cells (82). Consistent with these findings, conditional deletion of Shh in steroidogenic adrenocortical cells (under the Sf1 promoter) demonstrated marked adrenal hypoplasia, with the adrenal gland being 5-10 times smaller than the wild type but with a normal-sized medulla (83,84). Despite the clear size reduction with a thin capsule, the adrenal gland managed to maintain proper zonal organisation and steroidogenic cell differentiation (84).…”