WNT10A is a signaling molecule involved in tooth development, and WNT10A defects are associated with tooth agenesis. We characterized Wnt10a null mice generated by the knockout mouse project (KOMP) and six families with WNT10A mutations, including a novel p.Arg104Cys defect, in the absence of EDA,EDAR, or EDARADD variations. Wnt10a null mice exhibited supernumerary mandibular fourth molars, and smaller molars with abnormal cusp patterning and root taurodontism. Wnt10a−/− incisors showed distinctive apical–lingual wedge-shaped defects. These findings spurred us to closely examine the dental phenotypes of our WNT10A families. WNT10A heterozygotes exhibited molar root taurodontism and mild tooth agenesis (with incomplete penetrance) in their permanent dentitions. Individuals with two defective WNT10A alleles showed severe tooth agenesis and had fewer cusps on their molars. The misshapened molar crowns and roots were consistent with the Wnt10a null phenotype and were not previously associated with WNT10A defects. The missing teeth contrasted with the presence of supplemental teeth in the Wnt10a null mice and demonstrated mammalian species differences in the roles of Wnt signaling in early tooth development. We conclude that molar crown and root dysmorphologies are caused by WNT10A defects and that the severity of the tooth agenesis correlates with the number of defective WNT10A alleles.

Truncation mutations in FAM83H (family with sequence similarity 83, member H) cause autosomal dominant hypocalcified amelogenesis imperfecta (ADHCAI), but little is known about FAM83H function and the pathogenesis of ADHCAI. We recruited three ADHCAI families and identified two novel (p.Gln457*; p.Lys639*) and one previously documented (p.Q452*) disease‐causing FAM83H mutations. We generated and characterized Fam83h‐knockout/lacZ‐knockin mice. Surprisingly, enamel thickness, density, Knoop hardness, morphology, and prism patterns were similar in Fam83h +/+, Fam83h +/−, and Fam83h −/− mice. The histology of ameloblasts in all stages of development, in both molars and incisors, was virtually identical in all three genotypes and showed no signs of pathology, although the Fam83h −/− mice usually died after 2 weeks and rarely survived to 7 weeks. LacZ expression in the knockin mice was used to report Fam83h expression in the epithelial tissues of many organs, notably in skin and hair follicles, which manifested a disease phenotype. Pull‐down studies determined that FAM83H dimerizes through its N‐terminal phospholipase D‐like (PLD‐like) domain and identified potential FAM83H interacting proteins. Casein kinase 1 (CK1) interacts with the FAM83H PLD‐like domain via an F270‐X‐X‐X‐F274‐X‐X‐X‐F278 motif. CK1 can phosphorylate FAM83H in vitro, and many phosphorylation sites were identified in the FAM83H C‐terminus. Truncation of FAM83H alters its subcellular localization and that of CK1. Our results support the conclusion that FAM83H is not necessary for proper dental enamel formation in mice, but may act as a scaffold protein that localizes CK1. ADHCAI is likely caused by gain‐of‐function effects mediated by truncated FAM83H, which potentially mislocalizes CK1 as part of its pathological mechanism.

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Defects in WDR72 (WD repeat-containing protein 72) cause autosomal recessive hypomaturation amelogenesis imperfecta. We generated and characterized Wdr72-knockout/lacZ-knockin mice to investigate the role of WDR72 in enamel formation. In all analyses, enamel formed by Wdr72 heterozygous mice was indistinguishable from wild-type enamel. Without WDR72, enamel mineral density increased early during the maturation stage but soon arrested. The null enamel layer was only a tenth as hard as wild-type enamel and underwent rapid attrition following eruption. Despite the failure to further mineralize enamel deposited during the secretory stage, ectopic mineral formed on the enamel surface and penetrated into the overlying soft tissue. While the proteins in the enamel matrix were successfully degraded, the digestion products remained inside the enamel. Interactome analysis of WDR72 protein revealed potential interactions with clathrin-associated proteins and involvement in ameloblastic endocytosis. The maturation stage mandibular incisor enamel did not stain with methyl red, indicating that the enamel did not acidify beneath ruffle-ended ameloblasts. Attachment of maturation ameloblasts to the enamel layer was weakened, and SLC24A4, a critical ameloblast calcium transporter, did not localize appropriately along the ameloblast distal membrane. Fewer blood vessels were observed in the papillary layer supporting ameloblasts. Specific WDR72 expression by maturation stage ameloblasts explained the observation that enamel thickness and rod decussation (established during the secretory stage) are normal in the Wdr72 null mice. We conclude that WDR72 serves critical functions specifically during the maturation stage of amelogenesis and is required for both protein removal and enamel mineralization.

Objective: To compare the safety of sleeve gastrectomy and gastric bypass in a large cohort of commercially insured bariatric surgery patients from the IBM MarketScan claims database, while accounting for measurable and unmeasurable sources of selection bias in who is chosen for each operation. Summary of Background Data: Sleeve gastrectomy has rapidly become the most common bariatric operation performed in the United States, but its longer-term safety is poorly described, and the risk of worsening gastroesophageal reflux requiring revision may be higher than previously thought. Prior studies comparing sleeve gastrectomy to gastric bypass are limited by low sample size (in randomized trials) and selection bias (in observational studies). Methods: Instrumental variables analysis of commercially insured patients in the IBM MarketScan claims database from 2011 to 2018. We studied patients undergoing bariatric surgery from 2012 to 2016. We identified re-interventions and complications at 30 days and 2 years from surgery using Comprehensive Procedural Terminology and International Classification of Disease (ICD)-9/10 codes. To overcome unmeasured confounding, we use the prior year's sleeve gastrectomy utilization within each state as an instrumental variable-exploiting variation in the timing of payers' decisions to cover sleeve gastrectomy as a natural experiment. Results: Among 38,153 patients who underwent bariatric surgery between 2012 and 2016, the share of sleeve gastrectomy rose from 52.6% (2012) to 75% (2016). At 2 years from surgery, patients undergoing sleeve gastrectomy had fewer re-interventions (sleeve 9.9%, bypass 15.6%, P < 0.001) and complications (sleeve 6.6%, bypass 9.6%, P ¼ 0.001), and lower overall healthcare spending ($47,891 vs $55,213, P ¼ 0.003), than patients undergoing gastric bypass. However, at the 2-year mark, revisions were slightly more common in sleeve gastrectomy than in gastric bypass (sleeve 0.6%, bypass 0.4%, P ¼ 0.009). Conclusions and Relevance: In a large cohort of commercially insured patients, sleeve gastrectomy had a superior safety profile to gastric bypass up to 2 years from surgery, even when accounting for selection bias. However, the higher risk of revisions in sleeve gastrectomy merits further exploration.

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Under normal conditions, the regeneration of mouse β cells is mainly dependent on their own duplication. Although there is evidence that pancreatic progenitor cells exist around duct, whether non-β cells in the islet could also potentially contribute to β cell regeneration in vivo is still controversial. Here, we developed a novel transgenic mouse model to study the pancreatic β cell regeneration, which could specifically inhibit β cell proliferation by overexpressing p21 cip in β cells via regulation of the Tet-on system. We discovered that p21 overexpression could inhibit β-cell duplication in the transgenic mice and these mice would gradually suffer from hyperglycemia. Importantly, the recovery efficiency of the p21-overexpressing mice from streptozotocin-induced diabetes was significantly higher than control mice, which is embodied by better physiological quality and earlier emergence of insulin expressing cells. Furthermore, in the islets of these streptozotocin-treated transgenic mice, we found a large population of proliferating cells which expressed pancreatic duodenal homeobox 1 (PDX1) but not markers of terminally differentiated cells. Transcription factors characteristic of early pancreatic development, such as Nkx2.2 and NeuroD1, and pancreatic progenitor markers, such as Ngn3 and c-Met, could also be detected in these islets. Thus, our work showed for the first time that when β cell self-duplication is repressed by p21 overexpression, the markers for embryonic pancreatic progenitor cells could be detected in islets, which might contribute to the recovery of these transgenic mice from streptozotocin-induced diabetes. These discoveries could be important for exploring new diabetes therapies that directly promote the regeneration of pancreatic progenitors to differentiate into islet β cells in vivo.

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