[Role of Fibroblast Growth Factor 7 in Craniomaxillofacial Development]. / æˆçº¤ç»´ç»†èƒžç”Ÿé•¿å› å­7åœ¨é¢ é¢Œé¢å‘è‚²ä¸­çš„ä½œç”¨.

Craniomaxillofacial development involves a series of highly ordered temporal-spatial cellular differentiation processes in which a variety of cell signaling factors, such as fibroblast growth factors, play important regulatory roles. As a classic fibroblast growth factor, fibroblast growth factor 7 (FGF7) serves a wide range of regulatory functions. Previous studies have demonstrated that FGF7 regulates the proliferation and migration of epithelial cells, protects them, and promotes their repair. Furthermore, recent findings indicate that epithelial cells are not the only ones subjected to the broad and powerful regulatory capacity of FGF7. It has potential effects on skeletal system development as well. In addition, FGF7 plays an important role in the development of craniomaxillofacial organs, such as the palate, the eyes, and the teeth. Nonetheless, the role of FGF7 in oral craniomaxillofacial development needs to be further elucidated. In this paper, we summarized the published research on the role of FGF7 in oral craniomaxillofacial development to demonstrate the overall understanding of FGF7 and its potential functions in oral craniomaxillofacial development.

Effects of low occlusal loading on the neuromuscular behavioral development of cortically-elicited jaw movements in growing rats.

The effect of altered occlusal force on masticatory-related neuromuscular control, which projects from the anterior part of the cortical masticatory area (A-CMA), during growth remains unclear. This study sought to evaluate the effect of occlusal hypofunction on neuromuscular development of jaw muscle activities and cortically-induced rhythmic jaw movements (RJMs) in growing rats. Sixty-four 2-week-old male albino Wistar rats were divided into the control (fed normal diet) and experimental (fed soft diet) groups soon after weaning. Electromyographic activity was recorded at 5, 7, 9, and 11 weeks from the right masseter and anterior digastric along with RJMs. We found a significantly longer onset latency and smaller peak-to-peak amplitude in the experimental group than that in the control group. The RJMs showed an increase in gape size and lateral excursion until up to 9 weeks in both groups. However, both the average gape size and lateral excursion were significantly smaller in the experimental group than that in the control group after 9 weeks. The jaw movement pattern also showed a significant decrease at the maximum opening period in the experimental group. Our findings indicate that inadequate occlusal function during growth alters neuromuscular control of masticatory behaviors and impairs the pattern of RJMs.

Bayesian approach to longitudinal craniofacial growth: The Craniofacial Growth Consortium Study.

Early in the 20th century, a series of studies were initiated across North America to investigate and characterize childhood growth. The Craniofacial Growth Consortium Study (CGCS) combines craniofacial records from six of those growth studies (15,407 lateral cephalograms from 1,913 individuals; 956 females, 957 males, primarily European descent). Standard cephalometric points collected from the six studies in the CGCS allows direct comparison of craniofacial growth patterns across six North American locations. Three assessors collected all cephalometric points and the coordinates were averaged for each point. Twelve measures were calculated from the averaged coordinates. We implemented a multilevel double logistic equation to estimate growth trajectories fitting each trait separately by sex. Using Bayesian inference, we fit three models for each trait with different random effects structures to compare differences in growth patterns among studies. The models successfully identified important growth milestones (e.g., age at peak growth velocity, age at cessation of growth) for most traits. In a small number of cases, these milestones could not be determined due to truncated age ranges for some studies and slow, steady growth in some measurements. Results demonstrate great similarity among the six growth studies regarding craniofacial growth milestone estimates and the overall shape of the growth curve. These similarities suggest minor variation among studies resulting from differences in protocol, sample, or possible geographic variation. The analyses presented support combining the studies into the CGCS without substantial concerns of bias. The CGCS, therefore, provides an unparalleled opportunity to examine craniofacial growth from childhood into adulthood.

Biomarkers of fetal conditions: Finger ridge-counts, facial fluctuating asymmetry, and digit ratio (2D:4D)-are they correlated in women?

OBJECTIVES: Fetal environmental conditions are crucial for life-long health. Direct measurements of developmental conditions are limited in humans; thus, several biomarkers of those conditions have been proposed: that is, finger ridge-counts, level of facial fluctuating asymmetry (FA), and digit ratio (2D:4D). Since all of these biomarkers share a similar gestational time of formation, we hypothesize that their values are significantly correlated. MATERIALS AND METHODS: Data were collected at the Mogielica Human Ecology Study Site in southern Poland among 234 women. Finger ridge-counts, level of facial FA, and 2D:4D have been measured. The two-step analyses included Pearson's correlations of simple values of the biomarkers and correlations of composite variables calculated based on principal component analysis. RESULTS: We did not find any statistically significant correlations between finger ridge-counts, FA, and 2D:4D in women. Similarly, we did not observe any correlations between three composites created from the biomarkers. DISCUSSION: Our results indicate that there are no relationships between the biomarkers, suggested as proxies of the quality of prenatal conditions, in a single population. This is the first study analyzing three different markers simultaneously. The lack of correlations may indicate that the tested biomarkers reflect, in fact, different environmental conditions, occurring in separate "critical windows" of development, or that the biomarkers are not valid as proxies of developmental conditions.

Specialized Craniofacial Anatomy of a Titanosaurian Embryo from Argentina.

The first dinosaur embryos found inside megaloolithid eggs from Auca Mahuevo, Patagonia, were assigned to sauropod dinosaurs that lived approximately 80 million years ago. Discovered some 25 years ago, these considerably flattened specimens still remain the only unquestionable embryonic remains of a sauropod dinosaur providing an initial glimpse into titanosaurian in ovo ontogeny. Here we describe an almost intact embryonic skull, which indicates the early development of stereoscopic vision, and an unusual monocerotic face for a sauropod. The new fossil also reveals a neurovascular sensory system in the premaxilla and a partly calcified braincase, which potentially refines estimates of its prenatal stage. The embryo was found in an egg with thicker eggshell and a partly different geochemical signature than those from the egg-bearing layers described in Auca Mahuevo. The cranial bones are comparably ossified as in previously described specimens but differ in facial anatomy and size. The new specimen reveals significant heterochrony in cranial ossifications when compared with non-sauropod sauropodomorph embryos, and demonstrates that the specialized craniofacial morphology preceded the postnatal transformation of the skull anatomy in adults of related titanosaurians.

Vessel-derived angiocrine IGF1 promotes Meckel's cartilage proliferation to drive jaw growth during embryogenesis.

Craniofacial development is a complex morphogenic process that requires highly orchestrated interactions between multiple cell types. Blood vessel-derived angiocrine factors are known to promote proliferation of chondrocytes in Meckel's cartilage to drive jaw outgrowth, however the specific factors controlling this process remain unknown. Here, we use in vitro and ex vivo cell and tissue culture, as well as genetic mouse models, to identify IGF1 as a novel angiocrine factor directing Meckel's cartilage growth during embryonic development. We show that IGF1 is secreted by blood vessels and that deficient IGF1 signalling underlies mandibular hypoplasia in Wnt1-Cre; Vegfafl/fl mice that exhibit vascular and associated jaw defects. Furthermore, conditional removal of IGF1 from blood vessels causes craniofacial defects including a shortened mandible, and reduced proliferation of Meckel's cartilage chondrocytes. This demonstrates a crucial angiocrine role for IGF1 during craniofacial cartilage growth, and identifies IGF1 as a putative therapeutic for jaw and/or cartilage growth disorders.

Relación entre los patrones de crecimiento facial y la maduración dental y esquelética en los pacientes en crecimiento / Relationship between facial growth patterns and dental and skeletal maturation in growing patients

El objetivo de este trabajo es realizar una revisión bibliográfica para evaluar la posible relación entre los patrones de crecimiento facial con la maduración dental y esquelética en pacientes en crecimiento. La maduración dental y esquelética son dos indicadores que nos permiten es-tablecer en qué momento del desarrollo se encuentra el paciente en crecimiento. Actualmente, para la valoración de la maduración esquelética se emplea la visualización de las vértebras cervicales en la radiografía lateral de cráneo, ya que es un método que permite disminuir la exposición radiológica del paciente que se encuentra en estudio ortodóncico, en comparación con la radiografía de muñe-ca, la cual suponía la realización de una radiografía adicional. Para el análisis de la maduración dental, la radiografía panorámica es la más empleada mediante la visualización del desarrollo de los siete dientes mandibulares izquierdos. Los pacientes que se encuentran en edad infantil presentan diversos patrones de crecimiento facial, entre los que podemos encontrar, braquifacial, mesofacial y dolicofacial. Para poder establecer el patrón de crecimiento que presenta el paciente existen diversos métodos que, a través de mediciones cefalométricas, nos clasifican al paciente en uno de los tres grupos. Existen diversos trabajos que estudian la posible relación entre los patrones de crecimiento facial y la maduración dental y esquelética. Según la literatura revisada podemos concluir que los pacientes que presentan un patrón de crecimiento vertical muestran una maduración dental y esquelética más avanzada en comparación con los pacientes que presentan un patrón de crecimiento horizontal

The objective of this paper is to present a bibliographical review to evaluate the possible relationship between facial growth patterns and dental and skeletal maturation in growing patients.Dental and skeletal maturation are two indicators that allow us to establish at what point the patient is in his growth. Currently, for the evaluation of skeletal maturation, the visualisation of the cervical vertebrae in the lateral x-ray of the skull is used, since this is a method that diminishes the radiological exposure of the patient undergoing an orthodontic study, in comparison with the x-ray of the wrist, which means taking an additional x-ray.For the analysis of dental maturation, the panoramic x-ray is the most used through visualisation of the development of the seven left jaw teeth. Children in young ages present different facial growth patterns, among which we can find brachyfacial, mesofacial and dolichofacial. In order to establish the growth pattern the patient presents, there are different methods that, through cephalometric measurements, classify the patient in one of the three groups. Different papers study the possible relationship between facial growth patterns and dental and skeletal maturation. According to the reviewed literature, we can conclude that the patients who present a vertical growth pattern show more advanced dental and skeletal maturation in comparison with the patients who present a horizontal growth pattern

Morphometric variations and growth of the profile of the face in Chinese boys aged 4-15 years.

Much research has been conducted on the morphological growth and development of Chinese children. However, very few facial measurements have been documented, especially of the sagittal plane of the face. Morphometric variations and growth of the sagittal plane of the face in children were analyzed using geometric morphometric method in this study. The studied sample consisted of 108 boys (4-15 years) from Huzhu County in Qinghai Province of China, which were divided into three groups: 4-6 years old, 7-11 years old and 12-15 years old. It was revealed that the landmark-groups of nose area were relatively long, indicating large variation in the direction of the nasal protuberance, which possibly reflected the vigorous growth of the children's nose. There were larger landmark-groups' variability ranges in children aged 7-11 years, which may be related to the rapid growth in this period. The average morphology of the sagittal plane of the face changed a lot with age, which was showed in the comparison of the averaged graph of three groups: (1) the proportion of the forehead to entire face became smaller; (2) the 7th landmark extruded more noticeably; (3) the nose became protruding; (4) the position of the mouth was relatively getting more upward, and the angle formed between the upper lip and the lower lip increased, and the lower lip moved forward; (5) the chin protuberated. Principal Component Analysis (PCA) revealed significant differences in the main distribution areas between age group 4-6 years and 12-15 years, even though there was a lot of overlap in the three age groups. Allometric analysis showed that the sagittal plane of the face aged 4-6 years and 7-11 years changed in the following way as the size increased: the forehead became vertical and the upper lip turned to be smaller. Additionally, as the size increased in age group 12-15 years, the most prominent landmark of the forehead became more conspicuous, and the bridge of the nose got more upturned. These may reflect the common morphological features and growing development of the facial sagittal plane of Chinese children.

Odontoma complejo: resolución de un caso con utilización de osteosíntesis rígida por riesgo de fractura mandibular / Complex odontoma: case resolution with the use of rigid osteosynthesis for risk of mandibular fracture

Objetivo: Describir la resolución de un caso un odontoma complejo de gran tamaño con utilización de osteosíntesis rígida. Caso clínico: Una paciente de 13 años de edad se presentó a la consulta por aumento de volumen en hemifacia izquierda, de 4 meses de evolución. Mediante biopsia incisional, se diagnosticó odontoma complejo. Se realizó tratamiento quirúrgico con utilización de osteosíntesis rígida. Se decidió retirar la placa de osteosíntesis a los 6 meses posoperatorios para evitar alterar el crecimiento y el desarrollo mandibular. Se indicó control posoperatorio durante 5 años. Conclusión: La utilización de osteosíntesis rígida fue adecuada para reforzar el defecto óseo mandibular producido durante el tratamiento quirúrgico de un odontoma complejo de gran tamaño (AU)

Aim: To describe the resolution of a case of a large complex odontoma with the use of rigid osteosynthesis. Clinical case: A 13-year-old patient presented with a swelling in left jaw of 4 months of evolution. Complex odontoma was diagnosed by incisional biopsy. Surgical treatment was performed with the use of rigid osteosynthesis. Removal of osteosynthesis plate was decided 6 months postoperatively to avoid alteration of mandibular growth and development. Postoperative control was indicated for 5 years. Conclusion: The use of rigid osteosynthesis was adequate to reinforce the mandibular bone defect produced during the surgical treatment of large complex odontoma (AU)

Thyroid hormone modulation during zebrafish development recapitulates evolved diversity in danionin jaw protrusion mechanics.

Protrusile jaws are a highly useful innovation that has been linked to extensive diversification in fish feeding ecology. Jaw protrusion can enhance the performance of multiple functions, such as suction production and capturing elusive prey. Identifying the developmental factors that alter protrusion ability will improve our understanding of fish diversification. In the zebrafish protrusion arises postmetamorphosis. Fish metamorphosis typically includes significant changes in trophic morphology, accompanies a shift in feeding niche and coincides with increased thyroid hormone production. We tested whether thyroid hormone affects the development of zebrafish feeding mechanics. We found that it affected all developmental stages examined, but that effects were most pronounced after metamorphosis. Thyroid hormone levels affected the development of jaw morphology, feeding mechanics, shape variation, and cranial ossification. Adult zebrafish utilize protrusile jaws, but an absence of thyroid hormone impaired development of the premaxillary bone, which is critical to jaw protrusion. Premaxillae from early juvenile zebrafish and hypothyroid adult zebrafish resemble those from adults in the genera Danionella, Devario, and Microdevario that show little to no jaw protrusion. Our findings suggest that evolutionary changes in how the developing skulls of danionin minnows respond to thyroid hormone may have promoted diversification into different feeding niches.

The Influence of Four Different Treatment Protocols on Maxillofacial Growth in Patients with Unilateral Complete Cleft Lip, Palate, and Alveolus.

BACKGROUND: The purpose of this study was to evaluate the effect of four different treatment protocols on maxillofacial growth in patients aged 7 to 8 years with unilateral complete cleft lip, palate, and alveolus. METHODS: Sixty-one patients with nonsyndromic unilateral complete cleft lip, palate, and alveolus were entered into this study and grouped as follows: group 1 patients had a repaired lip and an unrepaired palate; group 2 patients underwent one-stage palatoplasty; group 3 patients underwent two-stage palatoplasty; and group 4 patients underwent lip adhesion and two-stage palatoplasty. The control group was composed of 16 patients with unilateral incomplete cleft lip. The Kolmogorov-Smirnov test was used to test the nature of data distribution. The Bonferroni test and the Kruskal-Wallis H test were used for multiple comparisons. RESULTS: Group 5 showed a more protruding maxilla (basion-nasion-A point, basion-nasion-anterior nasal spine, sella-nasion-anterior nasal spine; p < 0.05), longer maxillary sagittal length (anterior nasal spine-posterior maxillary point; p < 0.05) and maxillary basal sagittal length (A point-posterior maxillary point; p < 0.05), and a better jaw relationship (A point-nasion-B point angle; p < 0.05) than groups 2, 3, and 4. Group 2 had higher anterior facial height (anterior nasal spine-nasion, anterior nasal spine-menton, nasion-menton; p < 0.05) and posterior facial height (registration point-posterior maxillary point; p < 0.05) than groups 3 and 4. Groups 2 and 3 had better maxillary position (sella-pterygomaxillary fissure; p < 0.05) and deeper bony pharynx (basion-posterior maxillary point; p < 0.05) than group 4. CONCLUSIONS: In patients aged 7 to 8 years with unilateral complete cleft lip, palate, and alveolus, both one- and two-stage palatoplasty inhibited maxillary sagittal growth. Vomer flap repair with denuded bone inhibited maxillary vertical growth. Lip adhesion did adversely affect maxilla position. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Applicability of a pre-established set of facial proportions from frontal photographs in forensic age estimation of a Brazilian population.

Child pornography on the internet is one of the crimes with highest increasing incidence worldwide. In this specific type of crime, the victim's age has important legal implications. To overcome the lack of scientifically established protocols, European researchers explored and proposed a set of facial proportions obtained from images to estimate age. Within a validation scope, the present study aimed to test the applicability of morphological proportions from frontal photographs of the face to estimate age in a Brazilian population. Standardized frontal view photographs from 800 Brazilians (400 females and 400 males) homogeneously distributed in 4 age groups (6, 10, 14 and 18 years ± 30 days) were randomly selected from a Civilian Database of the Brazilian Federal Police. The selected images were analyzed with the aid of cephalometric landmarks. After landmarking the photographs, eighteen metric relations pre-established by Cattaneo et al. (C. Cattaneo, Z. Obertová, M. Ratnayake, L. Marasciuolo, J. Tutkuviene, P. Poppa, D. Gibelli, P. Gabriel, S. Ritz-Timme, Can facial proportions taken from images be of use for ageing in cases of suspected child pornography? A pilot study, Int. J. Leg. Med. 126 2012 139-144) were assessed and analyzed through parametric statistical tests and discriminant analysis. Two indexes had a moderate correlation with age, while ten had a weak correlation and six were not correlated with age. Eleven indexes were statistically different between sexes (p < 0.05). The discriminant analysis showed that 49.6% of the pooled sample was correctly classified into the respective age group. This percentage increased when each sex was analyzed separately: 50.2% for females and 53.5% for males. The set of facial proportions from frontal images proposed by Cattaneo et al. (2012) is related to facial development. As expected, the discriminant power of this approach did not reach optimal effectiveness in the Brazilian sample. In practice, this age estimation method must be adapted for more reliable application in Brazilians.

Dental implants in growing patients: a systematic review.

The aim of this systematic review (for which we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines) was to provide an overview of the protocols and clinical outcomes of dental implants placed in growing jaws. We searched the MEDLINE/PubMed, Embase, Scopus, and Science Direct databases in October and November, 2017. A total of 3492 studies were identified, and all the studies reporting the outcomes of dental implants placed during the growth phase were included in the study. After duplicates had been removed, 2133 studies were screened based on their titles and abstracts, and 162 were selected for reading. Finally, 28 studies were included in the review. Overall, 493 dental implants were placed in 147 patients aged from 3-18 years old with follow-up being from 1-20 years. The most common disorders seen that were associated with missing teeth were ectodermal dysplasia and dental trauma. The main complications reported were the infraocclusion positioning of dental implants in the maxillary arch and the rotation of dental implants in the mandibular arch. Dental implants were indicated for the anterior regions of the maxilla and mandible in patients over 10 years old, and placement of maxillary implants in a more coronal position was recommended. Consultations and adjustments to prostheses were required until growth had ceased. In growing jaws, dental implants require positional modifications, and they should be considered only under special circumstances.

Simulation of facial growth based on longitudinal data: Age progression and age regression between 7 and 17 years of age using 3D surface data.

Modelling of the development of facial morphology during childhood and adolescence is highly useful in forensic and biomedical practice. However, most studies in this area fail to capture the essence of the face as a three-dimensional structure. The main aims of our present study were (1) to construct ageing trajectories for the female and male face between 7 and 17 years of age and (2) to propose a three-dimensional age progression (age -regression) system focused on real growth-related facial changes. Our approach was based on an assessment of a total of 522 three-dimensional (3D) facial scans of Czech children (39 boys, 48 girls) that were longitudinally studied between the ages of 7 to 12 and 12 to 17 years. Facial surface scans were obtained using a Vectra-3D scanner and evaluated using geometric morphometric methods (CPD-DCA, PCA, Hotelling's T2 tests). We observed very similar growth rates between 7 and 10 years in both sexes, followed by an increase in growth velocity in both sexes, with maxima between 11 and 12 years in girls and 11 to 13 years in boys, which are connected with the different timing of the onset of puberty. Based on these partly different ageing trajectories for girls and boys, we simulated the effects of age progression (age regression) on facial scans. In girls, the mean error was 1.81 mm at 12 years and 1.7 mm at 17 years. In boys, the prediction system was slightly less successful: 2.0 mm at 12 years and 1.94 mm at 17 years. The areas with the greatest deviations between predicted and real facial morphology were not important for facial recognition. Changes of body mass index percentiles in children throughout the observation period had no significant influence on the accuracy of the age progression models for both sexes.

Imaging study of midface growth with bone-borne trans-sutural distraction osteogenesis therapy in growing cleft lip and palate patients.

Trans-sutural distraction osteogenesis (TSDO) promotes midface growth in growing cleft lip and palate (CLP) patients with midfacial hypoplasia. The superficial skeletal changes after therapy revealed rotation advancement of the midfacial skeleton associated with differential displacement in each segment, but reports rarely focus on the changes of internal structures, including circummaxillary sutures, the maxillary tuberosity and the maxillary sinus, which may play a crucial role during this process. This study evaluated the computed tomographic (CT) images of 26 growing CLP patients who received bone-borne TSDO therapy. The results revealed that the most prominent new bone formation occurred in the pterygomaxillary suture and pushed the P-point forward. The maxillary first molar exhibited significantly greater advancement compared with the P-point due to the growth of the maxillary tuberosity. The contribution ratio values of the advancement of the maxillary tuberosity and P-point to the maxillary first molar were 26% and 74%, respectively, in UCLP and 25% and 75%, respectively, in BCLP. Furthermore, the maxillary sinus volume was also significantly increased. In conclusion, midface growth with bone-borne TSDO therapy depends on both secondary displacement promoted by sutural bone formation mainly in the pterygomaxillary suture and primary displacement by growth of the maxillary tuberosity and maxillary sinus volume.

How thyroid hormones and their inhibitors affect cartilage growth and shape in the frog Xenopus laevis.

Understanding how skeleton changes shape in ontogeny is fundamental to understanding how its shape diversifies in phylogeny. Amphibians pose a special case because their jaw and throat skeleton consists of cartilages that are dramatically reshaped midway through life to support new feeding and breathing styles. Although amphibian metamorphosis is commonly studied by immersing larvae in thyroid hormones (TH), how individual cartilages respond to TH is poorly understood. This study documents the effects of larval stage and TH type (T4 vs. T3), dose and deprivation on the size, shape and morphogenesis of the lower jaw and ceratohyal cartilages in the frog Xenopus laevis. It uses thyroid inhibitors to isolate the effects of each hormone at specific concentrations. It also deconstructs the TH responses into the effects on individual dimensions, and uses measures of percent change to eliminate the effects of body size and growth rate variation. As stage increases, T4 and T3 responses become increasingly similar to each other and to natural remodeling; the differences at low and intermediate stages result largely from abnormal responses to T3. Most notably, the beak-like lower jaw commonly observed at the lowest stage in other studies results largely from arrested growth of cartilage. TH responses are superimposed upon the growth typical for each stage so that cartilages can attain postmetamorphic shapes through dimensional changes that exceed those of natural metamorphosis. Using thyroid inhibitors alters the outcome of TH-induced remodeling, and T4 has almost the same capacity to induce metamorphic shape changes as T3. The results have implications for understanding how the starting shapes of larval elements affect morphogenesis, how chondrocytes behave to change cartilage shape, and how intracellular processing of TH might contribute to interspecific differences in shape change. Also, the data on animal mortality and which stages and doses most closely replicate natural remodeling have practical value for researchers who treat Xenopus tadpoles with TH.

A non-canonical JAGGED1 signal to JAK2 mediates osteoblast commitment in cranial neural crest cells.

During craniofacial development, cranial neural crest (CNC) cells migrate into the developing face and form bone through intramembranous ossification. Loss of JAGGED1 (JAG1) signaling in the CNC cells is associated with maxillary hypoplasia or maxillary bone deficiency (MBD) in mice and recapitulates the MBD seen in humans with Alagille syndrome. JAGGED1, a membrane-bound NOTCH ligand, is required for normal craniofacial development, and Jagged1 mutations in humans are known to cause Alagille Syndrome, which is associated with cardiac, biliary, and bone phenotypes and these children experience increased bony fractures. Previously, we demonstrated deficient maxillary osteogenesis in Wnt1-cre;Jagged1f/f (Jag1CKO) mice by conditional deletion of Jagged1 in maxillary CNC cells. In this study, we investigated the JAG1 signaling pathways in a CNC cell line. Treatment with JAG1 induced osteoblast differentiation and maturation markers, Runx2 and Ocn, respectively, Alkaline Phosphatase (ALP) production, as well as classic NOTCH1 targets, Hes1 and Hey1. While JAG1-induced Hes1 and Hey1 expression levels were predictably decreased after DAPT (NOTCH inhibitor) treatment, JAG1-induced Runx2 and Ocn levels were surprisingly constant in the presence of DAPT, indicating that JAG1 effects in the CNC cells are independent of the canonical NOTCH pathway. JAG1 treatment of CNC cells increased Janus Kinase 2 (JAK2) phosphorylation, which was refractory to DAPT treatment, highlighting the importance of the non-canonical NOTCH pathway during CNC cells osteoblast commitment. Pharmacologic inhibition of JAK2 phosphorylation, with and without DAPT treatment, upon JAG1 induction reduced ALP production and, Runx2 and Ocn gene expression. Collectively, these data suggest that JAK2 is an essential component downstream of a non-canonical JAG1-NOTCH1 pathway through which JAG1 stimulates expression of osteoblast-specific gene targets in CNC cells that contribute to osteoblast differentiation and bone mineralization.

Premaxilla: up to which age it remains separated from the maxilla by a suture, how often it occurs in children and adults, and possible clinical and therapeutic implications: Study of 1,138 human skulls

ABSTRACT Objective: To evaluate topographic and temporal aspects of premaxillary bone and premaxillary-maxillary suture, since they are fundamental anatomical elements little explored clinically. Methods: 1,138 human dry skulls were evaluated, of which 116 (10.19%) of the specimens were children, and 1,022 (89.81%) were adults. The skulls were photographed and the percentage of premaxillary-maxillary suture opening was determined. Subsequently the data were tabulated and submitted to statistical analysis, adopting a level of significance of 5%. Results: The progression of premaxillary suture closure from birth to 12 years of age was 3.72% per year. In 100% of the skulls up to 12 years, the premaxillary-maxillary suture open in the palatal region was observed, while 6.16% of adults presented different degrees of opening. Conclusions: The premaxilla exists in an independent way within the maxillary complex and the presence of the premaxilla-maxillary suture justifies the success of anteroposterior expansions to stimulate the growth of the middle third of the face, solving anatomical and functional problems.

RESUMO Objetivo: avaliar aspectos topográficos e temporais do osso pré-maxilar e da sutura pré-maxilar/maxilar, por serem elementos anatômicos fundamentais pouco explorados clinicamente. Métodos: foram avaliados 1.138 crânios secos humanos, sendo 116 (10,19%) dos espécimes crianças e 1.022 (89,81%) adultos. Os crânios foram fotografados e determinou-se a porcentagem de abertura da sutura pré-maxilar/maxilar. Posteriormente, os dados foram tabulados e submetidos a análise estatística, adotando-se nível de significância de 5%. Resultados: a progressão de fechamento da sutura pré-maxilar/maxilar do nascimento aos 12 anos de idade foi de 3,72% ao ano. Em 100% dos crânios até 12 anos, observou-se a sutura pré-maxilar/maxilar aberta na região palatina, enquanto 6,16% dos adultos apresentavam diferentes graus. Conclusões: a pré-maxila existe de forma independente dentro do complexo maxilar e a presença da sutura pré-maxilar / maxilar justifica o sucesso de expansões anteroposteriores para estimular o crescimento do terço médio da face, solucionando problemas anatômicos e funcionais.

FoxO6 regulates Hippo signaling and growth of the craniofacial complex.

The mechanisms that regulate post-natal growth of the craniofacial complex and that ultimately determine the size and shape of our faces are not well understood. Hippo signaling is a general mechanism to control tissue growth and organ size, and although it is known that Hippo signaling functions in neural crest specification and patterning during embryogenesis and before birth, its specific role in postnatal craniofacial growth remains elusive. We have identified the transcription factor FoxO6 as an activator of Hippo signaling regulating neonatal growth of the face. During late stages of mouse development, FoxO6 is expressed specifically in craniofacial tissues and FoxO6-/- mice undergo expansion of the face, frontal cortex, olfactory component and skull. Enlargement of the mandible and maxilla and lengthening of the incisors in FoxO6-/- mice are associated with increases in cell proliferation. In vitro and in vivo studies demonstrated that FoxO6 activates Lats1 expression, thereby increasing Yap phosphorylation and activation of Hippo signaling. FoxO6-/- mice have significantly reduced Hippo Signaling caused by a decrease in Lats1 expression and decreases in Shh and Runx2 expression, suggesting that Shh and Runx2 are also linked to Hippo signaling. In vitro, FoxO6 activates Hippo reporter constructs and regulates cell proliferation. Furthermore PITX2, a regulator of Hippo signaling is associated with Axenfeld-Rieger Syndrome causing a flattened midface and we show that PITX2 activates FoxO6 expression. Craniofacial specific expression of FoxO6 postnatally regulates Hippo signaling and cell proliferation. Together, these results identify a FoxO6-Hippo regulatory pathway that controls skull growth, odontogenesis and face morphology.