Additionally, there is evidence for the function of the extrinsic pathway earlier in development, where Caspase-6 (executioner) and Caspase-8 (initiator) expression was increased in pre-ameloblasts as compared to secretory ameloblasts (Liu et al., 2015). and alterations in apoptotic cell distribution in transgenic mouse models. These studies foster a deeper understanding how apoptotic cells affect cellular processes during normal odontogenesis, and how they contribute to dental disorders, which could lead to new avenues of treatment in the future. embryos, supernumerary teeth formed in the diastemal region because of decreased apoptosis in the vestigial primordium, in association with increased proliferation (Klein et al., 2006; Peterkov et al., 2009). Supernumerary tooth development was also initiated in (Vaahtokari et al., 1996; Jernvall et al., 1998; Shigemura et al., 2001; Nadiri et al., 2004, 2006; Svandova et al., 2018), with expression being dependent on (Bei et al., 2004). Interestingly, despite the increase in apoptotic cell numbers as the enamel knot is eliminated, the region of the tooth does not exhibit reduction in cell mass, presumably due to rapid replacement by highly proliferating cells that surround the enamel knot (Matalova et al., Trazodone HCl 2004). Furthermore, studies have suggested that the PEK may have cellular continuity with the SEK (Coin et al., 1999), which would necessitate that some cells of the PEK escape apoptosis. The Effect of Apoptosis on the Tooth Crown Shaping The folding of the inner enamel epithelium contributes to enamel cusp/ridge formation in mammals. The enamel knot itself is proposed to drive epithelial bending (Jernvall et al., 1994; Vaahtokari et al., 1996). As was mentioned above, SEKs appear quite late in development, during tooth germ transition from late cap to early bell stages, when future cusps distribution is set up (Jernvall et al., 1994; Thesleff et al., 2001). The suspected role of Trazodone HCl SEKs in tooth cusp formation was confirmed in the Tabby mutant mouse, where SEKs appear to fuse together in the molar, leading to a fewer number of tooth cusps in comparison to wild-type Trazodone HCl animals (Pispa et al., 1999). Species-specific cusp positions are determined by signaling from the enamel knots as well (Jernvall et al., 2000), with differences in the apoptotic cell distribution observed in teeth with dissimilar morphologies. In mice, there are a large number of apoptotic cells located in the inner enamel epithelium of the PEK, with only a few situated above this area, in the stratum intermedium (Vaahtokari et al., 1996; Li et al., 2016). In gerbils, which possess lophodont molars characterized by long ridges running between the buccal-lingual Trazodone HCl cusps, most of the apoptotic cells were found in deeper enamel organ area including the stratum intermedium, while almost no apoptotic cells were located in the inner enamel epithelium (Li et al., 2016). However, it is important to mention that the aforementioned study only analyzed early developmental stages and therefore SEKs were not fully formed yet, which should be more important for tooth morphogenesis (Li et al., 2016). Odontogenesis was also analyzed in voles, which exhibit long enamel ridges and diagonal cusp pattern similarly to gerbils. This is in contrast to mice, where crests were lost during evolution (Jernvall et al., 2000). Apoptotic cells in voles Rabbit polyclonal to DGCR8 also display different distribution pattern in comparison to mice, with the Trazodone HCl increased presence of apoptotic cells in the stellate reticulum, especially above the enamel knots (Setkova et al., 2006). However, again no later developmental stages with SEKs have been analyzed yet, and therefore their involvement in specific cusp patterning cannot be confirmed or ruled out. A specific distribution of apoptotic cells was also found during the folding of the inner enamel epithelium in reptiles, where distinct structures such as enamel ridges and enamel grooves arise. In veiled chameleon and ocelot gecko (Figure 2), apoptotic cells are located in the stellate reticulum cells individually or in small clusters immediately above the enamel ridge area (Landova Sulcova et al., 2020). In the distal teeth of chameleons, two enamel ridges are formed with two distinct clusters of TUNEL-positive cells found above each enamel ridge and central groove area between them devoid of apoptotic cells. Non-apoptotic cells adjacent to those undergoing apoptosis demonstrate altered morphology with their long axes pointing in the opposite direction (Landova Sulcova et al., 2020). Similar folding and shape alterations have been observed in cells located near apoptotic cells during epithelial morphogenesis in (Monier et al., 2015). In chameleons, a similar downregulation was observed in case.
