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
Citation
Cortes, M., Liu, S.Y., Kwan, W., Alexa, K., Goessling, W., North, T.E. (2015) Accumulation of the Vitamin D Precursor Cholecalciferol Antagonizes Hedgehog Signaling to Impair Hemogenic Endothelium Formation. Stem Cell Reports. 5:471-9.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping