The developmental origin and the specification of the adrenal cortex in humans and cynomolgus monkeys

Abstract

Development of the adrenal cortex, a vital endocrine organ, originates in the adrenogonadal primordium, a common progenitor for both the adrenocortical and gonadal lineages in rodents. In contrast, we find that in humans and cynomolgus monkeys, the adrenocortical lineage originates in a temporally and spatially distinct fashion from the gonadal lineage, arising earlier and more anteriorly within the coelomic epithelium. The adrenal primordium arises from adrenogenic coelomic epithelium via an epithelial-to-mesenchymal transition, which then progresses into the steroidogenic fetal zone via both direct and indirect routes. Notably, we find that adrenocortical and gonadal lineages exhibit distinct HOX codes, suggesting distinct anterior-posterior regionalization. Together, our assessment of the early divergence of these lineages provides a molecular framework for understanding human adrenal and gonadal disorders.

Reconstitution of human adrenocortical specification and steroidogenesis using induced pluripotent stem cells

“…Unexpectedly, we also identified minor off-target cell types including CLDN5 + KDR + endothelial-like cells and ASCL1 + GATA3 + PHOX2B + TH + DBH + sympathoadrenal-like cells of uncertain origin (Extended Data Fig. 6b, e) 12 . Notably, trajectory analyses also revealed two additional lineages that appear to project from PIM/CE-like cells, thus sharing their origin with adrenocortical lineages.…”

“…We have previously demonstrated that human fetal adrenal cortex strongly expresses DLK1, a membrane bound protein that negatively regulates NOTCH signaling 12,15 . Moreover, Sonic Hedgehog (SHH) is thought to be critical for adrenocortical development, and downstream genes of SHH are highly expressed in human fetal adrenal cortex 12,[19][20][21] . This motivated us to test the effect of DAPT (NOTCH inhibitor) and SHH on NT expression.…”

“…In the human fetus, organogenesis of the adrenal cortex starts with fate specification of the NR5A1 + GATA4adrenogenic coelomic epithelium (AdCE) within the WT1 + coelomic epithelium at 3-4 week post fertilization (wpf) 12 . These cells subsequently undergo dorsomedial migration and form a condensed blastematous structure, referred to as the adrenal primordium (AP), which is followed by establishment of two distinct zonal structures, the peripherally located definitive zone (DZ) with putative stem cell/progenitor potential, and the centrally located fetal zone (FZ) with steroidogenic potential by 8 wpf [12][13][14] . Our single cell RNA-seq analysis of human fetal adrenals has recently revealed the cellular and transcriptional dynamics during specification of adrenocortical lineages 12 .…”

Development and function of the fetal adrenal

“…E1 and E2 is then transported from the placenta into the maternal the 'transitional zone' (TZ), develops between the DZ and FZ after mid-gestation [38,39]. Pseudotemporal ordering of cell transcriptomes from human embryonic adrenal cells suggests that the DZ originates directly from cells of the AP, whereas the FZ can both derive from the AP or from DZ cells [8]. Finally, the FZ is destined to disappear by apoptosis soon after birth, resulting in an about 20-time decrease in adrenal mass from the 4-5 g full-term adrenal, and a rapid fall in the production of androgen precursors, namely dehydroepiandrosterone (DHEA) and dehydroepiandrosteronesulfate (DHEA-S) [40,41].…”

Prolactin as an adrenocorticotropic hormone: Prolactin signalling is a conserved key regulator of sexually dimorphic adrenal gland function in health and disease

“…These in vitro data are fully consistent with the higher SF-1 expression in FZ cells compared to DZ cells (Figure 2H). [72] Another factor limiting SF-1 activity prevalently in the DZ is the transcriptional repressor DAX-1/NR0B1. [73] (A) SF-1 was shown to activate expression of the rat PRLR gene in a steroidogenic cell line.…”