Functions of RARs and RXRs in vivo: Genetic dissection of the retinoid
signaling pathway
M. Mark and P. Chambon
Institut de Génétique et de Biologie
Moléculaire et Cellulaire (IGBMC) (CNRS/INSERM/ULP/Collège
de France), Institut Clinique de la Souris (ICS)
BP 10142, 67404 Illkirch Cedex, France
Abstract: Retinoids, the active metabolites of vitamin A, regulate
complex gene networks involved in vertebrate morphogenesis, growth,
cellular differentiation, and homeostasis. They are used for the treatment
of skin disorders and as chemopreventive agents for certain cancers.
Molecular biology and genetic studies performed during the last 15 years
in vitro, using either acellular systems or transfected cells, have
shown that retinoid actions are mediated through heterodimers between
the 8 major RARa, b,
and g; isoforms and the 6 major RXRa,
b and g isoforms
that belong to the nuclear receptor (NR) superfamily, and act as ligand-dependent
transcriptional regulators. Furthermore, RXRs not only heterodimerize
with RARs, but also with numerous other members of the NR superfamily.
As in vitro studies are carried out under nonphysiological conditions,
they only indicate what is possible, but not necessarily what is actually
occurring in vivo. Therefore, mutations have been introduced by homologous
recombination (HR) in F9 embryonal carcinoma (EC) cells, a cell-autonomous
system that differentiates in the presence of RA, in order to disrupt
RAR and RXR genes and establish their cellular and molecular functions
in RA-induced differentiation. However, genetic approaches in the animal
should be used to determine the function of retinoid receptors under
truly physiological conditions. HR in embryonic stem (ES) cells, has
therefore been used to generate null mutations of the various RARs and
RXRs in the mouse germline. As reviewed here, the generation of such
RAR and RXR germline mutations, combined with pharmacological approaches
to block the RA signaling pathway, has provided many valuable insights
on the developmental functions of RA receptors. However, due to (i)
the complexity in "hormonal" signaling through transduction by the multiple
RARs and RXRs, (ii) the functional redundancies (possibly artefactually
generated by the mutations) within receptor isotypes belonging to a
given gene family, and (iii) in utero or postnatal lethality of certain
germline null mutations, these genetic studies through germline mutagenesis
have failed to reveal many of the physiological functions of RARs and
RXRs, notably in adults. We conclude that spatio-temporally controlled
somatic mutations generated in animal models in given cell-types/tissues
and at chosen times during pre- and postnatal life, are required to
reveal the physiological and pathophysiological functions of the receptor
genes involved in the retinoid signaling pathway throughout the life
of the mouse.
*Report from a SCOPE/IUPAC project: Implication of
Endocrine Active Substances for Human and Wildlife (J. Miyamoto and
J.Burger, editors). Other reports are published in this issue,
pp. 1617-2615.
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