Neural regulation in tooth regeneration of Ambystoma mexicanum

Abstract

the presence of nerves is an important factor in successful organ regeneration in amphibians. the Mexican salamander, Ambystoma mexicanum, is able to regenerate limbs, tail, and gills when nerves are present. However, the nerve-dependency of tooth regeneration has not been evaluated. Here, we reevaluated tooth regeneration processes in axolotls using a three-dimensional reconstitution method called coMBi and found that tooth regeneration is nerve-dependent although the dentary bone is independent of nerve presence. the induction and invagination of the dental lamina were delayed by denervation. Exogenous Fgf2, Fgf8, and Bmp7 expression could induce tooth placodes even in the denervated mandible. our results suggest that the role of nerves is conserved and that fgf+Bmp signals play key roles in axolotl organ-level regeneration. the presence of nerves is an important factor in successful organ regeneration in amphibians. the Mexican salamander, Ambystoma mexicanum, is able to regenerate limbs, tail, and gills when nerves are present. However, the nervedependency of tooth regeneration has not been evaluated. Here, we reevaluated tooth regeneration processes in axolotls using a three-dimensional reconstitution method called coMBi and found that tooth regeneration is nerve-dependent although the dentary bone is independent of nerve presence. the induction and invagination of the dental lamina were delayed by denervation. Exogenous Fgf2, Fgf8, and Bmp7 expression could induce tooth placodes even in the denervated mandible. our results suggest that the role of nerves is conserved and that fgf+Bmp signals play key roles in axolotl organ-level regeneration. The ability to regenerate lost tissues or organs in human patients has long been eagerly desired. Teeth are among the organs for which a novel treatment allowing perfect regeneration would be extremely useful. Due to the unique and multifarious roles of the teeth and associated structures, there has been a sustained effort to find optimal ways to replace missing dentition over many centuries. Amphibian teeth have unique physiological features but maintain some structural and functional similarities to mammalian teeth 1,2. One of the most notable features of amphibian teeth is polyphyodonty. Through polyphyodonty, amphibians replace their teeth continuously during life, whereas each mammalian tooth has either one or two generations (mono-or diphyodonty). Amphibian tooth development has been described in some classic studies 3-10. As far as we know, Hertwig published the first study of amphibian tooth development 5. Recently, the literature on tooth regeneration in amphibians was reviewed 1. The dental lamina is induced from the oral epithelium. The dental lamina, which consists of two layers, invades into the oral mesenchyme. The distal region of the dental lamina interacts with mesenchymal cells and forms a cup that is composed of the outer dental epithelium and the inner dental epithelium. The inner dental epithelium differentiates into enamel organs. The mesenchymal ...

Comparing nerve‐mediated FGF signalling in the early initiation phase of organ regeneration across mutliple amphibian species

“…Tooth regeneration was investigated as an additional phenomenon besides mandibular regeneration. The trigeminal nerves provide axons to axolotl teeth and express Fgf genes in addition to the DRG neurons and the spinal cord (Makanae et al, 2020). Denervation of axons from the trigeminal ganglia resulted in a severe delay in tooth regeneration.…”

“…Ectopic expression of Fgf2, Fgf8, and Bmp7 can reverse the delay in tooth regeneration that is caused by denervation. However, denervation could not completely prevent tooth regeneration (Makanae et al, 2020). Denervation procedures in the axolotl regeneration study are usually accompanied by axon regrowth at the end.…”

“…Thus, nerve‐secreted factors, which play a role in tail blastema formation, require more investigation. Tooth regeneration is also depending on the presence of nerves (Makanae et al, 2020). Classical studies on tooth regeneration were completed in newts (Davit‐Béal et al, 2007; Goss & Stagg, 1958; Goss, 1969).…”

Correlative microscopy and block-face imaging (CoMBI) method for both paraffin-embedded and frozen specimens

“…This correlation can add molecular data to the 3D morphological data, although the molecular data are limited to 2D distribution. To date, the CoMBI-C system has been used in various research fields, such as 3D analysis of primordia of beetle horn 16 , 3D distribution analysis of myelinated fibers of human facial nerves 17 , 3D morphological analysis of polycystic kidney of knockout mice 18 , and 3D visualization of regenerating bones and cartilage of the axolotl jaw 19 . Through these collaborative studies and ongoing collaborations, we found that users of the conventional CoMBI-C system desired compatibility with not only frozen specimens but also paraffin-embedded specimens.…”

Osteoblasts pattern endothelium and somatosensory axons during zebrafish caudal fin organogenesis

“…For example, the development of cranial foramina, or passageways of the skull, has been proposed to rely on sensory nerves and vasculature to restrict ossification to discrete domains (Akbareian et al, 2015). Additionally, damage to bony structures results in mis-patterned, incomplete repair when the tissue is denervated, as observed in deer antlers (Suttie and Fennessy, 1985), mouse femurs (Chen et al, 2019), and axolotl teeth (Makanae et al, 2020). In humans with congenital insensitivity to pain, a condition arising from an incomplete peripheral nervous system, patients experience significant musculoskeletal disorders, including repeated fractures (Bar-On et al, 2002;Mifsud et al, 2019).…”