Adjacent M3 Research Articles

Human Molar Size Variation: Wisdom Teeth Just Don't Care?

The inhibitory cascade model (ICM) is a tenet of mammalian molar morphogenesis that predicts that a larger developing first molar (M1) results in a smaller and later-forming adjacent second (M2) and third (M3) molar. Recently, we have shown that late-developing M3s are also at higher risk of impaction, a common dental health concern worldwide. The mechanisms delaying M3 onset time are unclear.Here we tested the hypothesis that M1 crown size predicts M3 developmental timing and M3 eruption, based on a sample of young Western Canadian dental patients. We also tested the extent to which contemporary modern human molars conform to the ICM. We sampled retrospective cone beam computed tomography scans and panoramic radiographs taken for clinical diagnostic purposes of multi-ethnic patients aged 13-24 years residing in four Western Canadian municipalities. We studied 99 patients, sampling 327 quadrants from 57 girls and 42 boys, at two distinct times that allowed us to know if an M3 had properly erupted. Using Horos and Xoran i-Cat software, we scored permanent molar development using a 9-stage classification after Demirjian's system. We measured mesiodistal lengths of M1, M2 and M3 crowns. In SPSS v.25, we calculated a Generalized Estimating Equation model through a multivariable linear regression to test if M1 crown length (“size”) predicted M3 developmental timing and eruption status. We also tested other variables including jaw type (maxillary; mandibular). Significance was set to p<0.05. Unexpectedly, we identified 13 molar size ratio patterns occurring at different frequencies (e.g., M1>M2>M3 in only 31.6% of cases) that reflected whether molars were located in the maxilla versus the mandible. This pattern diversity included up to four patterns in the same person's mouth. Further, M3 size was predicted not by M1 size (Wald Chi-Square [Wald X2]=0.701, p=0.40) but by M2/M1 ratio and absolute M2 size (Wald X2=14.04, p=0.000). Relative to M1 crown length, if M2 crown length increased by 10%, the adjacent M3 crown lengthened by 7% (±3%), indicating that M2 increases “faster” than M3. Crown length ratios (M3:M1, M2:M1) did not predict M3 impaction (Wald X2=0.124, p=0.73) or M3 developmental stage (M2:M1, Wald X2=0.228, p=0.63; M3:M1, Wald X2=3.253, p=0.07). We conclude that M1 crown length does not predict early versus late M3 development or M3 eruption status. Thus, the ICM does not appear to be useful for predicting M3 impaction risk. Contemporary modern humans present several distinct molar size ratio patterns, indicating that Homo sapiens molar size is subject to oral quadrant-specific and jaw type-specific effects beyond inhibition from a developing M1.

Evaluation of Risk Factors for External Root Resorption and Dental Caries of Second Molars Associated With Impacted Third Molars

Impacted third molars (M3s) may lead to external root resorption (ERR) and dental caries (DC) in the adjacent secondmolars (M2s). The aim of this study was to identify the risk factors for ERR and DC in M2s associated with impacted M3s. We implemented a cross-sectional study and enrolled a sample composed of patients with M3s and M2s present and cone-beam computed tomography (CBCT) scans available for review. If there was contact between the M2 and the adjacent M3 and the border of radiolucency was more distinct, the case was considered ERR. Apart from that, the case was considered DC. Potential predictor variables were defined as age, gender, tooth location, M2-M3 contact, root development in M3, M3 inclination, M3 impaction type, and M3 follicular diameter.Outcomes of the study were DC and ERR in M2s. CBCT was used to detect the presence of DC and ERR in M2s. A total of 250 eligible images of M3s in the upper and lower jaws of 167 patients were included. The mean age of the patients with CBCT images available was 26.08±4years (range, 18 to 40), and 43.6% of the patients were men. Factors associated with a significantly increased frequency of ERR in M2s included maxillary location, presence of M2-M3 contact, and mesioangular inclination (P<.005). DC in M2s was significantly more likely to occur in those with absence of contact between M2 and M3 (P<.005). The results of this study showed an increased risk of ERR to be associated with maxillary molars, mesioangular inclination, and presence of M2-M3 contact. The variable associated with an increased risk of DC was the absence of M2-M3 contact.

Wisdom tooth developmental timing and eruption are independent of first molar size in a study of contemporary Canadian children

Background/ObjectiveThird molar (M3) impaction is a common dental health concern worldwide. Classically, M3 impaction risk is higher with reduced jaw space for M3 eruption. Recently, we have shown that late‐developing M3s are also at higher risk of impaction. The factors that influence M3 developmental timing remain enigmatic. Past work has indicated that the length of the developing first molar (M1) exerts an inhibitory effect, resulting in a smaller and later‐forming M2 and M3. Here we test the hypothesis that M1 crown size predicts M3 developmental timing (advanced, or delayed) and M3 eruption (vs. impaction) in a group of young Canadian dental patients.MethodsWe sampled retrospective cone beam computed tomography scans and panoramic radiographs taken for clinical diagnostic purposes of multi‐ethnic patients aged 6–24 years residing in Western Canada. Post‐exclusion criteria, we studied 99 patients, sampling 327 quadrants from 57 girls and 42 boys, at two distinct times that allowed us to know if an M3 had properly erupted. Using Horos and Xoran i‐Cat software, we scored permanent molar development using a 9‐stage classification after Demirjian’s system. We measured mesiodistal lengths of M1, M2 and M3 crowns. In SPSS v.25, we calculated a Generalized Estimating Equation model through a multivariable linear regression to test if M1 crown length predicted M3 developmental timing and eruption status. We also tested other variables including patient sex and jaw type (upper; lower). Significance was set to p&lt;0.05.ResultsCrown length ratios (M3:M1 by M2:M1) did not predict M3 impaction (Wald Chi‐Square [Wald X2]=0.124, p=0.73) or M3 developmental stage (M2:M1, Wald X2=0.228, p=0.63; M3:M1, Wald X2=3.253, p=0.07). Patient sex was not associated with either M3 developmental timing or eruption. Jaw type was significantly associated with M3 eruption status (Wald X2=13.573, p=0.000) but not with M3 developmental timing (Wald X2=0.644, p=0.42). Among the 12 different patterns of M1:M2:M3 ratios that we observed, 3 were significantly more prevalent in the mandible versus the maxilla. Relative to M1 crown length, if M2 crown length increased by 10%, the adjacent M3 crown lengthened by 7% (±3%), indicating that M2 increased “faster” than M3. Absolute M2 crown length significantly predicted M3 crown length (Wald X2=14.04, p=0.000) while absolute M1 crown length did not (Wald X2=0.701, p=0.40).ConclusionsM1 crown length does not predict early versus late M3 development or M3 eruption status, thus M1 does not appear to predispose a given M3 towards impaction. However, whether an M3 forms in the lower jaw or upper jaw does appear to increase impaction risk, but not by delaying M3 development. Instead of a local variable, some systemic factor likely regulates timing of human permanent molar development. Compared to past work in non‐human primates and other mammals, modern human children show a wider range of molar crown size ratios and thus greater phenotypic variation within the molar row, of which M2 crown length appears most labile.Support or Funding InformationUniversity of Saskatchewan Colleges of Dentistry &amp; Medicine, and the Natural Sciences &amp; Engineering Research Council of Canada.

De novo mutations in GRIN1 cause extensive bilateral polymicrogyria.

Polymicrogyria is a malformation of cortical development. The aetiology of polymicrogyria remains poorly understood. Using whole-exome sequencing we found de novo heterozygous missense GRIN1 mutations in 2 of 57 parent-offspring trios with polymicrogyria. We found nine further de novo missense GRIN1 mutations in additional cortical malformation patients. Shared features in the patients were extensive bilateral polymicrogyria associated with severe developmental delay, postnatal microcephaly, cortical visual impairment and intractable epilepsy. GRIN1 encodes GluN1, the essential subunit of the N-methyl-d-aspartate receptor. The polymicrogyria-associated GRIN1 mutations tended to cluster in the S2 region (part of the ligand-binding domain of GluN1) or the adjacent M3 helix. These regions are rarely mutated in the normal population or in GRIN1 patients without polymicrogyria. Using two-electrode and whole-cell voltage-clamp analysis, we showed that the polymicrogyria-associated GRIN1 mutations significantly alter the in vitro activity of the receptor. Three of the mutations increased agonist potency while one reduced proton inhibition of the receptor. These results are striking because previous GRIN1 mutations have generally caused loss of function, and because N-methyl-d-aspartate receptor agonists have been used for many years to generate animal models of polymicrogyria. Overall, our results expand the phenotypic spectrum associated with GRIN1 mutations and highlight the important role of N-methyl-d-aspartate receptor signalling in the pathogenesis of polymicrogyria.

Functional Roles of a Conserved Tryptophan at Subunit-Subunit Interfaces in NMDA Receptor Membrane Regions

NMDA receptors (NMDARs) are ionotropic glutamate receptors (iGluRs) characterized by channel block by extracellular magnesium (Mg2+o) and slow deactivation kinetics. NMDARs are typically composed of two GluN1 and two GluN2 (GluN2A-GluN2D) subunits. The transmembrane domain (TMD) of each subunit contains three membrane-spanning regions (M1, M3, and M4) and a pore lining re-entrant loop (M2). The M2 region of each NMDAR subunit contains a tryptophan (W) that is highly conserved: nearly all known mammalian iGluR subunits, several potassium channels, and iGluR-like proteins in phylogenetically distant organisms contain W at the homologous site. This highly conserved W is located in NMDARs at the interface between the M2 region and the adjacent M3 region. Previous work demonstrated that mutation of this highly-conserved W in the GluN2B subunit (W607) drastically decreased block by Mg2+o, while mutation of the homologous residue in the GluN2A subunit (W606) had a relatively minor effect (Williams et al., 1998 Mol Pharmacol 53, 933). Interestingly, mutating the homologous residue in GluN1 subunits (W608) also has little effect on Mg2+o block (Siegler Retchless et al., 2012 Nat Neurosci 15, 406). To further explore the function of the conserved W at subunit-subunit interfaces we used whole-cell recordings from recombinant receptors expressed in tsA201 cells. We examined GluN2A(W606) and GluN2B(W607) mutants expressed with wild-type GluN1 subunits or GluN1 subunits with mutations of M3 residues at the M2-M3 interface. We found that receptors containing mutations at both GluN2A(W606) and a residue in the adjacent interface-lining GluN1 M3 region dramatically decreased block by Mg2+o. We also examined GluN1(W608) mutants and observed profoundly slowed deactivation kinetics. Overall, these results suggest that the conserved W is broadly involved in channel properties and gating of NMDARs.

Electrostatic and aromatic microdomains within the binding-site crevice of the D2 receptor: contributions of the second membrane-spanning segment.

The binding-site of the dopamine D2 receptor, like that of other homologous G protein-coupled receptors, is contained within a water-accessible crevice formed among its seven membrane-spanning segments. Using the substituted cysteine accessibility method (SCAM), we previously mapped the residues in the third, fifth, sixth, and seventh membrane-spanning segments that contribute to the surface of this binding-site crevice. We have now mutated to cysteine, one at a time, 22 consecutive residues in the second membrane-spanning segment (M2) and expressed the mutant receptors in HEK 293 cells. Eleven of these mutants reacted with charged, hydrophilic, lipophobic, sulfhydryl-specific reagents, added extracellularly, and 9 of these 11 were protected from reaction by a reversible dopamine antagonist, sulpiride. We infer that the side chains of the residues at the 11 reactive loci (D80, L81, V83, V87, P89, W90, V91, V92, L94, E95, V96) are on the water-accessible surface of the binding-site crevice and that 9 of these are occluded by bound antagonist. The pattern of accessibility suggests an alpha-helical conformation. A broadening of the angle of accessibility near the binding site is consistent with the presence of a kink at Pro89. On the basis of the enhanced rates of reaction of positively charged sulfhydryl reagents, we infer the presence of an electrostatic microdomain composed of three acidic residues in M2 and the adjacent M3 that could attract and orient cationic ligands. Furthermore, based on the enhanced reactivity of the hydrophobic cation-containing reagent, we infer the presence of an aromatic microdomain formed between M2, M3, and M7.