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A beta 2RARE-LacZ transgene identifies retinoic acid-mediated transcriptional activation in distinct cutaneous sites
1Department of Dermatology, New England Medical Center, Boston, Massachusetts 02111.
Abstract:
Retinoic acid and its derivatives (retinoids) exert profound influences on epithelial growth differentiation in a variety of tissues, including the skin. How retinoic acid mediates these effects is not fully understood. The recent cloning of a series of nuclear receptors for retinoic acid (RARs) has demonstrated that these proteins can function as ligand-inducible transcriptional enhancing factors. Moreover, all receptors are members of the steroid/thyroid hormone multigene family. In vitro studies have demonstrated the expression of RAR alpha, RAR beta, and RAR gamma in various cell types found in the skin. While multiple isoforms exist for each of the three RARs, it is unclear where each of these receptors functions in vivo to mediate the tissue-specific effects of retinoic acid. As a first step in determining sites of retinoic acid-mediated transcriptional activation in the skin and its appendages, we developed a transgenic model in which the retinoic acid response element (RARE) of the RAR beta 2 isoform is linked to a beta-galactosidase reporter gene. Our observations consistently demonstrate that retinoic acid transcriptionally activates the beta 2RARE in distinct areas of the skin. Of interest, certain of these areas are known to contain stem cells. These data clearly demonstrate that this type of transgenic "reporter" model can be used to further define retinoic acid-regulated signal transduction pathways in the skin, as well as other complex tissues. Furthermore, these observations raise the possibility that transcriptional activation of RAR beta 2 may regulate the growth and differentiation programs of selected populations of stem cells in the skin and its appendages.
Insights
Retinoic acid (RA) influences skin cell growth and differentiation. A new transgenic model shows RA activates specific skin areas, potentially regulating stem cell programs.
Area of Science:
- Dermatology
- Molecular Biology
- Genetics
Background:
- Retinoic acid (RA) and its derivatives (retinoids) significantly impact epithelial cell growth and differentiation in tissues like the skin.
- The precise mechanisms by which RA mediates these effects are not fully elucidated.
- Nuclear receptors for retinoic acid (RARs), members of the steroid/thyroid hormone superfamily, act as ligand-inducible transcriptional enhancers.
Purpose of the Study:
- To investigate the in vivo localization and function of retinoic acid receptors (RARs) in the skin.
- To develop a tool for identifying sites of RA-mediated transcriptional activation in skin and its appendages.
- To explore the role of RAR beta 2 in regulating skin cell growth and differentiation.
Main Methods:
- Development of a transgenic mouse model.
- Linking the retinoic acid response element (RARE) from the RAR beta 2 isoform to a beta-galactosidase reporter gene.
- Utilizing the reporter gene to visualize sites of transcriptional activation in vivo.
Main Results:
- The transgenic model successfully identified distinct skin areas where retinoic acid transcriptionally activates the RAR beta 2 RARE.
- These activated areas notably include regions known to harbor stem cells.
- The study confirms the utility of transgenic reporter models for dissecting RA signaling pathways in complex tissues.
Conclusions:
- Transgenic reporter models are effective for mapping retinoic acid-mediated transcriptional activity in the skin.
- Transcriptional activation of RAR beta 2 occurs in specific skin regions, including stem cell niches.
- These findings suggest that RAR beta 2 activation may play a role in regulating the growth and differentiation of skin stem cells.