PUBLICATION

RBP4 Disrupts Vitamin A Uptake Homeostasis in a STRA6-Deficient Animal Model for Matthew-Wood Syndrome

Authors
Isken, A., Golczak, M., Oberhauser, V., Hunzelmann, S., Driever, W., Imanishi, Y., Palczewski, K., and von Lintig, J.
ID
ZDB-PUB-080309-28
Date
2008
Source
Cell Metabolism   7(3): 258-268 (Journal)
Registered Authors
Driever, Wolfgang
Keywords
none
MeSH Terms
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/metabolism*
  • Craniofacial Abnormalities/embryology
  • Craniofacial Abnormalities/metabolism
  • Acyltransferases/metabolism
  • Humans
  • Oligonucleotides, Antisense/metabolism
  • Time Factors
  • Abnormalities, Multiple/genetics
  • Abnormalities, Multiple/metabolism*
  • Eye/embryology
  • Eye/enzymology
  • Eye/metabolism
  • Mice
  • Gene Deletion
  • Syndrome
  • Cardiovascular Abnormalities/embryology
  • Cardiovascular Abnormalities/metabolism
  • Retinol-Binding Proteins, Plasma/genetics
  • Retinol-Binding Proteins, Plasma/metabolism*
  • Vitamin A/metabolism*
  • Disease Models, Animal
  • Transduction, Genetic
  • Membrane Proteins/genetics
  • Membrane Proteins/metabolism*
  • Animals
  • Tretinoin/metabolism
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
  • Morpholines/metabolism
  • Gene Expression Regulation, Developmental
  • Homeostasis
  • NIH 3T3 Cells
(all 34)
PubMed
18316031 Full text @ Cell Metab.
CTD
18316031
Abstract
The cellular uptake of vitamin A from its RBP4-bound circulating form (holo-RBP4) is a homeostatic process that evidently depends on the multidomain membrane protein STRA6. In humans, mutations in STRA6 are associated with Matthew-Wood syndrome, manifested by multisystem developmental malformations. Here we addressed the metabolic basis of this inherited disease. STRA6-dependent transfer of retinol from RBP4 into cultured NIH 3T3 fibroblasts was enhanced by lecithin:retinol acyltransferase (LRAT). The retinol transfer was bidirectional, strongly suggesting that STRA6 acts as a retinol channel/transporter. Loss-of-function analysis in zebrafish embryos revealed that Stra6 deficiency caused vitamin A deprivation of the developing eyes. We provide evidence that, in the absence of Stra6, holo-Rbp4 provokes nonspecific vitamin A excess in several embryonic tissues, impairing retinoic acid receptor signaling and gene regulation. These fatal consequences of Stra6 deficiency, including craniofacial and cardiac defects and microphthalmia, were largely alleviated by reducing embryonic Rbp4 levels by morpholino oligonucleotide or pharmacological treatments.
Genes / Markers
Figures
Figure Gallery (6 images)
Show all Figures
Expression
Phenotype
Fish Conditions Stage Phenotype Figure
AB/TLchemical treatment: N-phenylthioureaProtruding-mouth
AB/TL + MO1-stra6standard conditionsProtruding-mouth
AB/TL + MO1-stra6standard conditionsProtruding-mouth
AB/TL + MO1-stra6standard conditionsProtruding-mouth
AB/TL + MO1-stra6standard conditionsProtruding-mouth
AB/TL + MO1-stra6standard conditionsDay 4
AB/TL + MO2-stra6chemical treatment: N-phenylthioureaProtruding-mouth
AB/TL + MO2-stra6chemical treatment: N-phenylthioureaProtruding-mouth
AB/TL + MO2-stra6chemical treatment: N-phenylthioureaProtruding-mouth
AB/TL + MO2-stra6standard conditions20-25 somites
1 - 10 of 38
Show
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
y1TgTransgenic Insertion
    1 - 1 of 1
    Show
    Human Disease / Model
    Human Disease Fish Conditions Evidence
    syndromic microphthalmia 9AB/TL + MO1-stra6standard conditionsTAS
    syndromic microphthalmia 9AB/TL + MO2-stra6standard conditionsTAS
    syndromic microphthalmia 9AB/TL + MO3-stra6standard conditionsTAS
    1 - 3 of 3
    Show
    Sequence Targeting Reagents
    Target Reagent Reagent Type
    rbp4MO3-rbp4MRPHLNO
    stra6MO1-stra6MRPHLNO
    stra6MO2-stra6MRPHLNO
    stra6MO3-stra6MRPHLNO
    1 - 4 of 4
    Show
    Fish
    Fish
    AB/TL
    AB/TL + MO1-stra6
    AB/TL + MO2-stra6
    AB/TL + MO2-stra6 + MO3-rbp4
    AB/TL + MO3-rbp4
    AB/TL + MO3-stra6
    y1Tg
    y1Tg + MO2-stra6
    1 - 8 of 8
    Show
    Antibodies
    No data available
    Orthology
    No data available
    Engineered Foreign Genes
    Marker Marker Type Name
    EGFPEFGEGFP
    1 - 1 of 1
    Show
    Mapping
    No data available
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    Citation
    Isken, A., Golczak, M., Oberhauser, V., Hunzelmann, S., Driever, W., Imanishi, Y., Palczewski, K., and von Lintig, J. (2008) RBP4 Disrupts Vitamin A Uptake Homeostasis in a STRA6-Deficient Animal Model for Matthew-Wood Syndrome. Cell Metabolism. 7(3):258-268.