Abstract
Developmental signalling pathways are implicated in the formation and maintenance of the adrenal gland, but their roles are currently not well defined. In recent years it has emerged that Sonic hedgehog (Shh) and Wnt/β catenin signalling are crucial for the growth and development of the adrenal cortex. Here we demonstrate that Fibroblast growth factor receptor (Fgfr) 2 isoforms IIIb and IIIc are expressed mainly in the adrenal subcapsule during embryogenesis and that specific deletion of the Fgfr2 IIIb isoform impairs adrenal development, causing reduced adrenal growth and impaired expression of SF1 and steroidogenic enzymes. The hypoplastic adrenals also have thicker, disorganised capsules which retain Gli1 expression but no longer express Dlk1. Fgfr2 ligands were detected in both the capsule and the cortex, suggesting the importance of signalling between the capsule and the cortex in adrenal development.
Highlights
The adrenal cortex is the primary site of steroid synthesis, producing glucocorticoids under the control of the hypothalamic–pituitary–adrenal (HPA) axis and mineralocorticoids under the control of the renin-angiotensin system (RAS)
We investigated the expression of Fgfr2 isoforms IIIb and IIIc in e15.5 wild type (WT) mouse adrenals by non-radioactive in situ hybridization (NR-ISH) using isoform-specific probes (Fig. 1A–F): both IIIb and IIIc isoforms were expressed underneath the capsule in cells that do not express Cyp11b1
Germline knockout of the IIIb exon of the Fgfr2 gene results in mice that die at birth from multiple developmental defects, identifying Fgfr2 IIIb as a critical mediator of organogenesis
Summary
The adrenal cortex is the primary site of steroid synthesis, producing glucocorticoids under the control of the hypothalamic–pituitary–adrenal (HPA) axis and mineralocorticoids under the control of the renin-angiotensin system (RAS). Adrenocortical development originates in a group of cells lying between the urogenital ridge and the dorsal aorta, forming the precursors of the adrenal glands and the gonads, the adrenogonadal primordium (AGP) (Hatano et al, 1996). At around embryonic day e9.0 in the mouse these cells begin to express the steroidogenic transcription factor Steroidogenic Factor-1 (SF1), which is essential for both adrenal and gonadal development (Luo et al, 1994). By e12.0, cells of the dorsal medial AGP form the adrenocortical primordium which is invaded by migrating sympathetic neural crest cells that form the central adrenal medulla (Hatano et al, 1996). We and others have shown that sonic hedgehog (Shh) is expressed in relatively undifferentiated steroidogenic cells in the subcapsular region of the mouse
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