PMID- 16397886
OWN - NLM
STAT- MEDLINE
DCOM- 20060327
LR  - 20231213
IS  - 1542-0752 (Print)
IS  - 1542-0752 (Linking)
VI  - 76
IP  - 1
DP  - 2006 Jan
TI  - Role of retinoic acid receptors alpha1 and gamma in the response of murine limbs 
      to retinol in vitro.
PG  - 39-45
AB  - BACKGROUND: Derivatives of retinol (vitamin A), commonly referred to as 
      retinoids, signal through retinoic acid and retinoid X receptors (RARs/RXRs) and 
      are essential for normal limb formation. Retinoid imbalances or perturbations in 
      receptor function result in aberrant limb development. To examine the mechanisms 
      underlying retinol-induced limb defects, we determined the responsiveness of 
      limbs from RARalpha1-/-gamma mice to excess retinol in vitro. METHODS: 
      RARalpha1-/-gamma+/- mice were bred and their embryos were recovered at 
      gestational day (GD) 12.5. The forelimbs were excised and cultured in vitro in 
      the presence of all-trans retinol acetate (0, 1.25, 12.5, or 62.5 microM) for 6 
      days. The expression profiles of genes known to affect chondrogenesis (sox9 and 
      col2a1) and limb outgrowth (meis1, meis2, and pbx1a) were examined by real-time 
      qRT-PCR following retinol exposure for 3 hr. RESULTS: Whereas 
      RARalpha1-/-gamma+/+ and RARalpha1-/-gamma+/- limbs exhibited deleterious effects 
      on limb outgrowth and chondrogenesis in the presence of exogenous retinol, this 
      outcome was significantly attenuated in RARalpha1-/-gamma-/- limbs. The 
      expressions of sox9 and col2a1 were significantly decreased in retinol-exposed 
      RARalpha1-/-gamma+/+ limbs. In contrast, expression was not altered in limbs from 
      their RARalpha1-/-gamma+/- or RARalpha1-/-gamma-/- littermates. Retinol exposure 
      upregulated the expression of meis1 and meis2 in RARalpha1-/-gamma+/+ limbs; 
      however, in RARalpha1-/-gamma-/- limbs the expression of both genes was 
      unresponsive to retinol. Pbx1a remained unresponsive to retinol treatment in all 
      genotypes. CONCLUSION: In the absence of RARalpha1, RARgamma is a functionally 
      important mediator of retinoid-induced limb dysmorphogenesis.
CI  - Copyright (c) 2005 Wiley-Liss, Inc.
FAU - Galdones, Eugene
AU  - Galdones E
AD  - Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada.
FAU - Lohnes, David
AU  - Lohnes D
FAU - Hales, Barbara F
AU  - Hales BF
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Birth Defects Res A Clin Mol Teratol
JT  - Birth defects research. Part A, Clinical and molecular teratology
JID - 101155107
RN  - 0 (Col2a1 protein, mouse)
RN  - 0 (Collagen Type II)
RN  - 0 (High Mobility Group Proteins)
RN  - 0 (Rara protein, mouse)
RN  - 0 (Receptors, Retinoic Acid)
RN  - 0 (Retinoic Acid Receptor alpha)
RN  - 0 (SOX9 Transcription Factor)
RN  - 0 (Sox9 protein, mouse)
RN  - 0 (Teratogens)
RN  - 0 (Transcription Factors)
RN  - 11103-57-4 (Vitamin A)
SB  - IM
MH  - Analysis of Variance
MH  - Animals
MH  - Chondrogenesis/drug effects
MH  - Collagen Type II/metabolism
MH  - Extremities/embryology
MH  - Female
MH  - Gene Expression Regulation, Developmental/drug effects
MH  - Gestational Age
MH  - High Mobility Group Proteins/metabolism
MH  - Limb Deformities, Congenital/*chemically induced
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Organ Culture Techniques
MH  - Pregnancy
MH  - Receptors, Retinoic Acid/deficiency/genetics/*physiology
MH  - Retinoic Acid Receptor alpha
MH  - SOX9 Transcription Factor
MH  - Teratogens/*toxicity
MH  - Time Factors
MH  - Transcription Factors/metabolism
MH  - Up-Regulation/drug effects
MH  - Vitamin A/*toxicity
MH  - Retinoic Acid Receptor gamma
EDAT- 2006/01/07 09:00
MHDA- 2006/03/28 09:00
CRDT- 2006/01/07 09:00
PHST- 2006/01/07 09:00 [pubmed]
PHST- 2006/03/28 09:00 [medline]
PHST- 2006/01/07 09:00 [entrez]
AID - 10.1002/bdra.20219 [doi]
PST - ppublish
SO  - Birth Defects Res A Clin Mol Teratol. 2006 Jan;76(1):39-45. doi: 
      10.1002/bdra.20219.