| RRC ID |
66143
|
| 著者 |
Rydeen A, Voisin N, D'Aniello E, Ravisankar P, Devignes CS, Waxman JS.
|
| タイトル |
Excessive feedback of Cyp26a1 promotes cell non-autonomous loss of retinoic acid signaling.
|
| ジャーナル |
Dev Biol
|
| Abstract |
Teratogenic levels of retinoic acid (RA) signaling can cause seemingly contradictory phenotypes indicative of both increases and decreases of RA signaling. However, the mechanisms underlying these contradictory phenotypes are not completely understood. Here, we report that using a hyperactive RA receptor to enhance RA signaling in zebrafish embryos leads to defects associated with gain and loss of RA signaling. While the gain-of-function phenotypes arise from an initial increase in RA signaling, using genetic epistasis analysis we found that the loss-of-function phenotypes result from a clearing of embryonic RA that requires a rapid and dramatic increase in cyp26a1 expression. Thus, the sensitivity of cyp26a1 expression to increased RA signaling causes an overcompensation of negative feedback and loss of embryonic RA signaling. Additionally, we used blastula transplantation experiments to test if Cyp26a1, despite its cellular localization, can limit RA exposure to neighboring cells. We find that enhanced Cyp26a1 expression limits RA signaling in the local environment, thus providing the first direct evidence that Cyp26 enzymes can have cell non-autonomous consequences on RA levels within tissues. Therefore, our results provide novel insights into the teratogenic mechanisms of RA signaling and the cellular mechanisms by which Cyp26a1 expression can shape a RA gradient.
|
| 巻・号 |
405(1)
|
| ページ |
47-55
|
| 公開日 |
2015-9-1
|
| DOI |
10.1016/j.ydbio.2015.06.008
|
| PII |
S0012-1606(15)30013-0
|
| PMID |
26116175
|
| PMC |
PMC4529768
|
| MeSH |
Animals
Animals, Genetically Modified
Body Patterning
Cell Count
Cytochrome P-450 Enzyme System / metabolism*
Embryo, Nonmammalian / metabolism
Feedback, Physiological*
Injections
Myocytes, Cardiac / cytology
Receptors, Retinoic Acid / metabolism
Retinoic Acid 4-Hydroxylase
Signal Transduction*
Tretinoin / metabolism*
Zebrafish / embryology
Zebrafish / metabolism*
Zebrafish Proteins
|
| IF |
2.896
|
| リソース情報 |
| ゼブラフィッシュ |
giraffe rw716 |
