7 Retinoic Acid Signaling and the Zebrafish Dentition …
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expression have well-studied consequences for the anteroposterior (AP) identity of
repeating structures. Interestingly, it has long been known that RA has a remarkable
ability to upregulate the expression of Hox genes in certain developing tissues, and
several examples employing both RA inhibition or overexposure have been shown
to change the identity of structures along the AP axis such as with hindbrain rhombomeres (Maves and Kimmel 2005) and vertebrae (Houle et al. 2003). Several Hox
genes are expressed at the AP level of the posterior pharynx where teeth normally
form in zebrafish, and at least some of this expression is expanded anteriorly after 24
hpf RA exposure (Seritrakul et al. 2012). It is possible that at least part of the reason
that teeth expand anteriorly after RA exposure is due to a homeotic transformation
of anterior tissues due to overexpression of Hox genes driven by RA. However, some
attempts have been made to overexpress Hox genes directly to see if the zebrafish
dentition would expand anteriorly in a RA-independent manner, but they have thus
far proved unsuccessful, suggesting that RA might be doing more than simply upregulating Hox expression when anterior teeth are induced. Regardless, it is possible
that RA-induced changes to Hox expression may have played a role in changing
tooth location in evolution via homeotic mechanisms.
In addition to regulating Hox expression, RA has other well-characterized effects
on the patterning and differentiation of CNC cells (Manzanares et al. 2000; Minoux
and Rijli 2010). Therefore, it is interesting to consider a possible RA/CNC connection
in the context of the cartilage defects seen after exogenous RA application to zebrafish
and whether these changes might have anything to do directly with tooth development. In many different experiments, both with broadly applied exogenous RA or
with focal application via RA-coated beads, disruption of cartilage development has
correlated very tightly with supernumerary tooth formation (Seritrakul et al. 2012).
This observation led to the idea that perhaps excess RA is able to directly change
the fate of CNC cells that would normally form cartilage into that of odontoblasts,
and that these excess odontoblast precursors are able to induce supernumerary tooth
formation (Fig. 7.5). Classic transplantation experiments in other vertebrate species
have shown that at certain stages of tooth development, pre-odontoblast cells have
the ability to induce ectopic tooth formation (Balic and Thesleff 2015). Additionally,
it is possible that an excess of pre-odontoblasts generated by excess RA signaling is
sufficient to change the shape of teeth, given that it was recently determined that the
number of odontoblast cells within a zebrafish tooth germ correlates with the size
and shape of the subsequent tooth (Yu et al. 2015). Taken together with the previously studied connections between RA signaling and odontoblast/dentin formation
seen in the pioneering studies in rodent teeth, it seems plausible that RA control of
CNC specification may be a general feature of tooth development, at least in certain
vertebrate lineages.
189
expression have well-studied consequences for the anteroposterior (AP) identity of
repeating structures. Interestingly, it has long been known that RA has a remarkable
ability to upregulate the expression of Hox genes in certain developing tissues, and
several examples employing both RA inhibition or overexposure have been shown
to change the identity of structures along the AP axis such as with hindbrain rhombomeres (Maves and Kimmel 2005) and vertebrae (Houle et al. 2003). Several Hox
genes are expressed at the AP level of the posterior pharynx where teeth normally
form in zebrafish, and at least some of this expression is expanded anteriorly after 24
hpf RA exposure (Seritrakul et al. 2012). It is possible that at least part of the reason
that teeth expand anteriorly after RA exposure is due to a homeotic transformation
of anterior tissues due to overexpression of Hox genes driven by RA. However, some
attempts have been made to overexpress Hox genes directly to see if the zebrafish
dentition would expand anteriorly in a RA-independent manner, but they have thus
far proved unsuccessful, suggesting that RA might be doing more than simply upregulating Hox expression when anterior teeth are induced. Regardless, it is possible
that RA-induced changes to Hox expression may have played a role in changing
tooth location in evolution via homeotic mechanisms.
In addition to regulating Hox expression, RA has other well-characterized effects
on the patterning and differentiation of CNC cells (Manzanares et al. 2000; Minoux
and Rijli 2010). Therefore, it is interesting to consider a possible RA/CNC connection
in the context of the cartilage defects seen after exogenous RA application to zebrafish
and whether these changes might have anything to do directly with tooth development. In many different experiments, both with broadly applied exogenous RA or
with focal application via RA-coated beads, disruption of cartilage development has
correlated very tightly with supernumerary tooth formation (Seritrakul et al. 2012).
This observation led to the idea that perhaps excess RA is able to directly change
the fate of CNC cells that would normally form cartilage into that of odontoblasts,
and that these excess odontoblast precursors are able to induce supernumerary tooth
formation (Fig. 7.5). Classic transplantation experiments in other vertebrate species
have shown that at certain stages of tooth development, pre-odontoblast cells have
the ability to induce ectopic tooth formation (Balic and Thesleff 2015). Additionally,
it is possible that an excess of pre-odontoblasts generated by excess RA signaling is
sufficient to change the shape of teeth, given that it was recently determined that the
number of odontoblast cells within a zebrafish tooth germ correlates with the size
and shape of the subsequent tooth (Yu et al. 2015). Taken together with the previously studied connections between RA signaling and odontoblast/dentin formation
seen in the pioneering studies in rodent teeth, it seems plausible that RA control of
CNC specification may be a general feature of tooth development, at least in certain
vertebrate lineages.