Large-scale reprogramming of cranial neural crest gene expression by retinoic acid exposure.
| Title: | Large-scale reprogramming of cranial neural crest gene expression by retinoic acid exposure. |
|---|---|
| Authors: | Williams SS; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.; Mear JP; Liang HC; Potter SS; Aronow BJ; Colbert MC |
| Source: | Physiological genomics [Physiol Genomics] 2004 Oct 04; Vol. 19 (2), pp. 184-97. |
| Publication Type: | Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, P.H.S. |
| Language: | English |
| Journal Info: | Publisher: American Physiological Society Country of Publication: United States NLM ID: 9815683 Publication Model: Print Cited Medium: Internet ISSN: 1531-2267 (Electronic) Linking ISSN: 10948341 NLM ISO Abbreviation: Physiol Genomics Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Bethesda, MD : American Physiological Society, c1999- |
| MeSH Terms: | Gene Expression Regulation, Developmental/*drug effects ; Neural Crest/*chemistry ; Neural Crest/*metabolism ; Tretinoin/*pharmacology; Cell Adhesion/drug effects ; Cell Adhesion/genetics ; Cell Adhesion/physiology ; Cranial Nerve Injuries/chemically induced ; Down-Regulation/drug effects ; Down-Regulation/genetics ; Gene Expression Profiling/methods ; Gene Expression Profiling/statistics & numerical data ; Genes/drug effects ; Genes/physiology ; Genes, Immediate-Early/drug effects ; Genes, Immediate-Early/genetics ; Neural Crest/cytology ; Neural Crest/drug effects ; Neurons/metabolism ; Oligonucleotide Array Sequence Analysis/methods ; Oligonucleotide Array Sequence Analysis/statistics & numerical data ; Suppression, Genetic/drug effects ; Up-Regulation/drug effects ; Up-Regulation/genetics ; Animals ; Cells, Cultured ; Mice ; Time Factors |
| Abstract: | Although retinoic acid (RA), the active form of vitamin A, is required for normal embryonic growth and development, it is also a powerful teratogen. Infants born to mothers exposed to retinoids during pregnancy have a 25-fold increased risk for malformations, nearly exclusively of cranial neural crest-derived tissues. To characterize neural crest cell responses to RA, we exposed murine crest cultures to teratogenic levels of RA and subjected their RNA to microarray-based gene expression profile analysis using Affymetrix MG-U74Av2 GeneChips. RNAs were isolated from independent cultures treated with 10(-6) M RA for 6, 12, 24, or 48 h. Statistical analyses of gene expression profile data facilitated identification of the 205 top-ranked differentially regulated genes whose expression was reproducibly changed by RA over time. Cluster analyses of these genes across the independently treated sample series revealed distinctive kinetic patterns of altered gene expression. The largest group was transiently affected within the first 6 h of exposure, representing early responding genes. Group 2 showed sustained induction by RA over all times, whereas group 3 was characterized by the suppression of a time-dependent expression increase normally seen in untreated cells. Additional patterns demonstrated time-dependent increased or decreased expression among genes not normally regulated to a significant extent. Gene function analysis revealed that more than one-third of all RA-regulated genes were associated with developmental regulation, including both canonical and noncanonical Wnt signaling pathways. Multiple genes associated with cell adhesion and cell cycle regulation, recognized targets for the biological effects of RA, were also affected. Taken together, these results support the hypothesis that the teratogenic effects of RA derive from reprogramming gene expression of a host of genes, which play critical roles during embryonic development regulating pathways that determine subsequent differentiation of cranial neural crest cells. |
| Grant Information: | ES-11747 United States ES NIEHS NIH HHS; P01-HL-36059 United States HL NHLBI NIH HHS |
| Substance Nomenclature: | 5688UTC01R (Tretinoin) |
| Entry Date(s): | Date Created: 20041007 Date Completed: 20050818 Latest Revision: 20131121 |
| Update Code: | 20260130 |
| DOI: | 10.1152/physiolgenomics.00136.2004 |
| PMID: | 15466718 |
| Database: | MEDLINE |
Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, P.H.S.