4 RA Signaling in Limb Development and Regeneration …
111
been carried out to simulate gene regulatory networks in a growing limb bud in order
to explore different ways in which gradients of FGF and RA might regulate expression
of cyp26b1, meis, hoxa11 and hoxa13 (Uzkudun et al. 2015). The model was also
tested for responses to perturbations (exogenous application of RA, surgical removal
of the FGF source and genetic ectopic expression of meis1), This network revealed
a new model of PD regulation in which the proximal morphogen (RA) controls the
distal boundary of Hoxa11, while conversely the distal morphogens (FGFs) control
the proximal boundary. This area is in its infancy and much work needs to be done
for confirmation of the model.
Relevance
While studies on limb development have highlighted that RA is in one location in
the embryo and acts elsewhere (perhaps through a concentration gradient), little is
known about the details of the processes nor about the mechanics of generating and
maintaining a gradient of RA. Many questions remain: What is the molecular basis
for the release of RA from cells? Is it transported through the extracellular matrix
(ECM) with a carrier like it is in the blood? Free diffusion of such a lipophilic and
toxic compound seems counterintuitive. How is RA taken up by cells? Is there an
RA equivalent of STRA6, the membrane receptor of retinol? Answers to these sorts
of embryological questions will provide an important impact to retinoid biology.
The Future
Studies across many vertebrate model systems, such as those summarized here,
immediately raise questions about the evolution of RA signaling mechanisms and
the evolution of the organ being studied. What we have seen here, not only in anamniotes, but also in the mouse, is that, unlike the forelimb, the hindlimbs may be
initiated differently or develop in the absence of RA. Considering the presumed evolutionary origin of limbs from a common fin fold, this raises fascinating questions
about the validity of this hypothesis. After all, the pelvic fins/hindlimbs of zebrafish
and urodeles develop at completely different times from each other, and, as a result,
there are far fewer studies on them. Mouse limb buds develop at the same time, yet
the forelimb depends upon an initial RA stimulus, and the hindlimb does not. Does
this mean that the limb buds have developed/evolved independently? The missing
group in the vertebrate model systems represented here are the reptiles. It would be
interesting to study the role of RA in the development of reptilian limb buds from
this perspective.
Acknowledgements I wish to thank Nicole Serrano for her excellent drawing skills displayed in
Fig. 4.3.
111
been carried out to simulate gene regulatory networks in a growing limb bud in order
to explore different ways in which gradients of FGF and RA might regulate expression
of cyp26b1, meis, hoxa11 and hoxa13 (Uzkudun et al. 2015). The model was also
tested for responses to perturbations (exogenous application of RA, surgical removal
of the FGF source and genetic ectopic expression of meis1), This network revealed
a new model of PD regulation in which the proximal morphogen (RA) controls the
distal boundary of Hoxa11, while conversely the distal morphogens (FGFs) control
the proximal boundary. This area is in its infancy and much work needs to be done
for confirmation of the model.
Relevance
While studies on limb development have highlighted that RA is in one location in
the embryo and acts elsewhere (perhaps through a concentration gradient), little is
known about the details of the processes nor about the mechanics of generating and
maintaining a gradient of RA. Many questions remain: What is the molecular basis
for the release of RA from cells? Is it transported through the extracellular matrix
(ECM) with a carrier like it is in the blood? Free diffusion of such a lipophilic and
toxic compound seems counterintuitive. How is RA taken up by cells? Is there an
RA equivalent of STRA6, the membrane receptor of retinol? Answers to these sorts
of embryological questions will provide an important impact to retinoid biology.
The Future
Studies across many vertebrate model systems, such as those summarized here,
immediately raise questions about the evolution of RA signaling mechanisms and
the evolution of the organ being studied. What we have seen here, not only in anamniotes, but also in the mouse, is that, unlike the forelimb, the hindlimbs may be
initiated differently or develop in the absence of RA. Considering the presumed evolutionary origin of limbs from a common fin fold, this raises fascinating questions
about the validity of this hypothesis. After all, the pelvic fins/hindlimbs of zebrafish
and urodeles develop at completely different times from each other, and, as a result,
there are far fewer studies on them. Mouse limb buds develop at the same time, yet
the forelimb depends upon an initial RA stimulus, and the hindlimb does not. Does
this mean that the limb buds have developed/evolved independently? The missing
group in the vertebrate model systems represented here are the reptiles. It would be
interesting to study the role of RA in the development of reptilian limb buds from
this perspective.
Acknowledgements I wish to thank Nicole Serrano for her excellent drawing skills displayed in
Fig. 4.3.