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Mesectoderm is a major target of retinoic acid action
M Mark1, N B Ghyselinck, P Kastner
1I.G.B.M.C., CNRS/INSERM/ULP/Collège de France, Illkirch. igbmc@igbmc.u-strasbg.fr
Abstract:
The RAR and RXR families of retinoid nuclear receptors each comprise three isotypes (alpha, beta and gamma). In vitro, RARs bind to their cognate DNA response elements as heterodimers with RXRs. Null mutations of all six isotypes have been generated. The defects displayed by RAR alpha, beta and gamma single null mutant mice are confined to a small subset of the tissues normally expressing these receptors. This discrepancy reflects the existence of a functional redundancy, since RAR double null mutants exhibit congenital malformations in almost every organ system. In particular, most of the structures derived from the mesectoderm are severely affected. Analysis of mutant mice lacking both RARs and RXRs indicates that RXR alpha:RAR gamma heterodimers are instrumental in the patterning of craniofacial skeletal elements, whereas RXR alpha:RAR alpha heterodimers may be preferentially involved in the generation of neural crest cell-derived arterial smooth muscle cells. Both RXR alpha:RAR beta and RXR alpha:RAR gamma heterodimers appear to function during the development of the ocular mesenchyme. Moreover, atavistic reptilian cranial structures are generated in RAR mutants, suggesting that the RA signal has been implicated in the modification of developmental programs in the mesectoderm during evolution.
Insights
Retinoic acid receptors (RARs) and retinoid X receptors (RXRs) are crucial for development. Functional redundancy among these receptors influences mesectoderm development and evolutionary modifications.
Area of Science:
- Molecular biology
- Developmental biology
- Genetics
Background:
- Retinoid nuclear receptors, including Retinoic Acid Receptors (RARs) and Retinoid X Receptors (RXRs), play vital roles in cellular differentiation and development.
- Each receptor family has three isotypes (alpha, beta, gamma), and they function as heterodimers in vitro.
- Understanding the in vivo functions of these receptors is critical for deciphering developmental pathways.
Purpose of the Study:
- To investigate the functional redundancy and specific roles of RAR and RXR isotypes in mammalian development.
- To elucidate the contribution of different RXR-RAR heterodimers to specific developmental processes, particularly in mesectoderm-derived structures.
- To explore the evolutionary implications of retinoic acid signaling in developmental program modification.
Main Methods:
- Generation and analysis of mice with null mutations in all six RAR and RXR isotypes (single, double, and combined null mutants).
- Phenotypic analysis of mutant mice to identify congenital malformations and developmental defects.
- Comparative analysis of defects across different mutant genotypes to infer functional redundancy and heterodimer-specific roles.
Main Results:
- Single RAR null mutations caused limited defects, indicating functional redundancy.
- RAR double null mutants exhibited severe, widespread congenital malformations, especially affecting mesectoderm-derived structures.
- Specific RXR-RAR heterodimers were implicated in craniofacial patterning (RXRα:RARγ), arterial smooth muscle development (RXRα:RARα), and ocular mesenchyme development (RXRα:RARβ, RXRα:RARγ).
Conclusions:
- Functional redundancy among RAR and RXR isotypes is essential for normal development, particularly for mesectoderm formation.
- Distinct RXR-RAR heterodimers have specialized roles in patterning specific embryonic structures.
- Retinoic acid signaling has influenced evolutionary modifications of developmental programs in the mesectoderm.