Non-cell-autonomous retinoid signaling is crucial for renal development

Abstract

SUMMARYIn humans and mice, mutations in the Ret gene result in Hirschsprung's disease and renal defects. In the embryonic kidney, binding of Ret to its ligand, Gdnf, induces a program of epithelial cell remodeling that controls primary branch formation and branching morphogenesis within the kidney. Our previous studies showed that transcription factors belonging to the retinoic acid (RA) receptor family are crucial for controlling Ret expression in the ureteric bud; however, the mechanism by which retinoid-signaling acts has remained unclear. In the current study, we show that expression of a dominant-negative RA receptor in mouse ureteric bud cells abolishes Ret expression and Ret-dependent functions including ureteric bud formation and branching morphogenesis, indicating that RA-receptor signaling in ureteric bud cells is crucial for renal development. Conversely, we find that RA-receptor signaling in ureteric bud cells depends mainly on RA generated in nearby stromal cells by retinaldehyde dehydrogenase 2, an enzyme required for most fetal RA synthesis. Together, these studies suggest that renal development depends on paracrine RA signaling between stromal mesenchyme and ureteric bud cells that regulates Ret expression both during ureteric bud formation and within the developing collecting duct system.

Mutations in GREB1L Cause Bilateral Kidney Agenesis in Humans and Mice

“…22,23 GREB1L has been reported as a target of retinoic acid signaling, a pathway that is crucial for renal development and the dysregulation of which has been proposed as a causative mechanism for urinary tract malformations. 13,[24][25][26] The recent identification of GREB1L mutations in two families with renal agenesis 27 highlighted this gene as a major actor of kidney differentiation. In order to characterize the pattern of GREB1L expression, we first used cDNA panels from various human fetal and adult tissues.…”

“…RET, a crucial regulator of UB branching, has been reported as a target of retinoic acid signaling. 24 Whether Greb1l plays a role in regulation of this gene will need to be established.…”

Mesenchymal Cells Regulate Retinoic Acid Receptor-Dependent Cortical Thymic Epithelial Cell Homeostasis

“…RA is a major physiological regulator of epithelial cell homeostasis in multiple organs such as the lung (28), kidney (29), pancreas (30), gut (31), and skin (32). Regarding thymus development, mesenchyme-derived RDH10-and RALDH2-dependent RA signaling in the pharyngeal arch endoderm, a region that gives rise to TEC progenitors, is a critical prerequisite to the initial formation of the thymus (26,33,34).…”

Development of the kidney medulla

“…Besides forming adult interstitium, stroma modulates glomerulogenesis and UB branching in the developing metanephros. 54,60,61 The contribution of stroma to morphogenesis of renal medulla is demonstrated by aberrant medullary development in mice that are deficient in genes expressed exclusively in the stroma ( Table 1). Kidneys of Foxd1-null mice have a reduced number of UB branches and ectopic mesenchymal condensates in the medulla.…”

“…57 Combined absence of RA receptors RAR a and β2 or retinaldehyde dehydrogenase 2 causes formation of small kidneys with reduced number of UB branches. 61,63 In Pod1-null mice, fibroblast-like spindle-shaped stromal cells are absent and renal medulla does not form. 64 Similar phenotype is observed in mice that lack a homeodomain transcription factor Pbx1.…”