Chapter 4
RA Signaling in Limb Development
and Regeneration in Different Species
Malcolm Maden
Abstract This chapter brings together data on the role of retinoic acid (RA) in the
embryonic development of fins in zebrafish, limbs in amphibians, chicks, and mice,
and regeneration of the amphibian limb. The intention is to determine whether there
is a common set of principles by which we can understand the mode of action of RA
in both embryos and adults. What emerges from this synthesis is that there are indeed
commonalities in the involvement of RA in processes that ventralize, posteriorize,
and proximalize the developing and regenerating limb. Different axes of the limb
have historically been studied independently; as for example, the embryonic development of the anteroposterior (AP) axis of the chick limb bud versus the regeneration
of the limb bud proximodistal (PD) axis. But when we take a broader view, a unifying
principle emerges that explains why RA administration to embryos and regenerating limbs results in the development of multiple limbs in both cases. As might be
expected, different molecular pathways govern the development of different systems
and model organisms, but despite these differences, the pathways involve similar RA
signaling genes, such as tbx5, meis, shh, fgfs and hox genes. Studies of developing
and regenerating systems have highlighted that RA acts by being synthesized in one
embryonic location while acting in another one, exactly as embryonic morphogens
do, although there is no evidence for the presence of an RA gradient within the limb.
What also emerges is that there is a paucity of information on the involvement of
RA in development of the dorsoventral (DV) axis. A molecular explanation as to
how RA establishes and alters positional information in all three axes is the most
important area of study for the future.
Keywords Retinoic acid · Signaling · Regenerating · Embryonic · Development ·
Limb · Limb bud · Blastema · Fin · Mouse · Chick · Amphibians · Fish ·
Xenopus · Axolotl · Morphogens · Gradient · Axes · Zone of polarizing activity ·
ZPA
M. Maden (B)
Department of Biology, Department of Biology, UF Genetics Institute, University of Florida,
Gainesville, USA
e-mail: malcmaden@ufl.edu
© Springer Nature Switzerland AG 2020
M. A. Asson-Batres and C. Rochette-Egly (eds.), The Biochemistry of Retinoid
Signaling III, Subcellular Biochemistry 95,
https://doi.org/10.1007/978-3-030-42282-0_4
87
RA Signaling in Limb Development
and Regeneration in Different Species
Malcolm Maden
Abstract This chapter brings together data on the role of retinoic acid (RA) in the
embryonic development of fins in zebrafish, limbs in amphibians, chicks, and mice,
and regeneration of the amphibian limb. The intention is to determine whether there
is a common set of principles by which we can understand the mode of action of RA
in both embryos and adults. What emerges from this synthesis is that there are indeed
commonalities in the involvement of RA in processes that ventralize, posteriorize,
and proximalize the developing and regenerating limb. Different axes of the limb
have historically been studied independently; as for example, the embryonic development of the anteroposterior (AP) axis of the chick limb bud versus the regeneration
of the limb bud proximodistal (PD) axis. But when we take a broader view, a unifying
principle emerges that explains why RA administration to embryos and regenerating limbs results in the development of multiple limbs in both cases. As might be
expected, different molecular pathways govern the development of different systems
and model organisms, but despite these differences, the pathways involve similar RA
signaling genes, such as tbx5, meis, shh, fgfs and hox genes. Studies of developing
and regenerating systems have highlighted that RA acts by being synthesized in one
embryonic location while acting in another one, exactly as embryonic morphogens
do, although there is no evidence for the presence of an RA gradient within the limb.
What also emerges is that there is a paucity of information on the involvement of
RA in development of the dorsoventral (DV) axis. A molecular explanation as to
how RA establishes and alters positional information in all three axes is the most
important area of study for the future.
Keywords Retinoic acid · Signaling · Regenerating · Embryonic · Development ·
Limb · Limb bud · Blastema · Fin · Mouse · Chick · Amphibians · Fish ·
Xenopus · Axolotl · Morphogens · Gradient · Axes · Zone of polarizing activity ·
ZPA
M. Maden (B)
Department of Biology, Department of Biology, UF Genetics Institute, University of Florida,
Gainesville, USA
e-mail: malcmaden@ufl.edu
© Springer Nature Switzerland AG 2020
M. A. Asson-Batres and C. Rochette-Egly (eds.), The Biochemistry of Retinoid
Signaling III, Subcellular Biochemistry 95,
https://doi.org/10.1007/978-3-030-42282-0_4
87