PUBLICATION

Accumulation of the Vitamin D Precursor Cholecalciferol Antagonizes Hedgehog Signaling to Impair Hemogenic Endothelium Formation

Authors
Cortes, M., Liu, S.Y., Kwan, W., Alexa, K., Goessling, W., North, T.E.
ID
ZDB-PUB-161129-10
Date
2015
Source
Stem Cell Reports   5: 471-9 (Journal)
Registered Authors
Goessling, Wolfram, North, Trista
Keywords
none
MeSH Terms
  • Animals
  • Cholecalciferol/metabolism
  • Cholecalciferol/pharmacology*
  • Cholestanetriol 26-Monooxygenase/genetics
  • Cholestanetriol 26-Monooxygenase/metabolism
  • Gene Deletion
  • Hedgehog Proteins/metabolism*
  • Hematopoiesis/drug effects*
  • Hematopoietic Stem Cells/cytology
  • Hematopoietic Stem Cells/drug effects*
  • Receptors, G-Protein-Coupled/metabolism
  • Signal Transduction/drug effects
  • Vitamins/metabolism
  • Vitamins/pharmacology*
  • Zebrafish/embryology*
  • Zebrafish/genetics
  • Zebrafish/metabolism
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed
26365513 Full text @ Stem Cell Reports
Abstract
Hematopoietic stem and progenitor cells (HSPCs) are born from hemogenic endothelium in the dorsal aorta. Specification of this hematopoietic niche is regulated by a signaling axis using Hedgehog (Hh) and Notch, which culminates in expression of Runx1 in the ventral wall of the artery. Here, we demonstrate that the vitamin D precursor cholecalciferol (D3) modulates HSPC production by impairing hemogenic vascular niche formation. Accumulation of D3 through exogenous treatment or inhibition of Cyp2r1, the enzyme required for D3 25-hydroxylation, results in Hh pathway antagonism marked by loss of Gli-reporter activation, defects in vascular niche identity, and reduced HSPCs. Mechanistic studies indicated the effect was specific to D3, and not active 1,25-dihydroxy vitamin D3, acting on the extracellular sterol-binding domain of Smoothened. These findings highlight a direct impact of inefficient vitamin D synthesis on cell fate commitment and maturation in Hh-regulated tissues, which may have implications beyond hemogenic endothelium specification.
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Errata and Notes