Wnt Signaling Drives Correlated Changes in Facial Morphology and Brain Shape.
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ABSTRACT:
SUBMITTER: Marchini M
PROVIDER: S-EPMC8039397 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionThe regular collection of 3-dimensional (3D) imaging data is critical to the development and implementation of accurate predictive models of facial skeletal growth. However, repeated exposure to x-ray-based modalities such as cone-beam computed tomography has unknown risks that outweigh many potential benefits, especially in pediatric patients. One solution is to make inferences about the facial skeleton from external 3D surface morphology captured using safe nonionizing imaging modalities alone. However, the degree to which external 3D facial shape is an accurate proxy of skeletal morphology has not been previously quantified. As a first step in validating this approach, we tested the hypothesis that population-level variation in the 3D shape of the face and skeleton significantly covaries.MethodsWe retrospectively analyzed 3D surface and skeletal morphology from a previously collected cross-sectional cone-beam computed tomography database of nonsurgical orthodontics patients and used geometric morphometrics and multivariate statistics to test the hypothesis that shape variation in external face and internal skeleton covaries.ResultsExternal facial morphology is highly predictive of variation in internal skeletal shape ([Rv] = 0.56, P <0.0001; partial least squares [PLS] 1-13 = 98.7% covariance, P <0.001) and asymmetry (Rv = 0.34, P <0.0001; PLS 1-5 = 90.2% covariance, P <0.001), whereas age-related (r(2) = 0.84, P <0.001) and size-related (r(2) = 0.67, P <0.001) shape variation was also highly correlated.ConclusionsSurface morphology is a reliable source of proxy data for the characterization of skeletal shape variation and thus is particularly valuable in research designs where reducing potential long-term risks associated with radiologic imaging methods is warranted. We propose that longitudinal surface morphology from early childhood through late adolescence can be a valuable source of data that will facilitate the development of personalized craniodental and treatment plans and reduce exposure levels to as low as reasonably achievable.
| S-EPMC4813327 | biostudies-literature
Project description:BackgroundThorough understanding of developmental changes of human facial shape is lacking. The present study aimed to evaluate developmental shape changes of facial morphology based on a prospective, population-representative, Chinese cohort in Hong Kong.MethodsA population-representative sample of Chinese in Hong Kong was followed. Serial facial images of over 260 participants were obtained at age 12, 15, and 18 years. Facial landmarks were digitized and the corresponding coordinates were submitted for Generalized Procrustes Analysis. The resultant Procrustes shape coordinates, which captured shape information encoded by the facial landmarks, were then used for statistical shape analyses.ResultsSmall but significant developmental changes in mean facial shape were observed (p < 0.0001 for all pairwise comparisons). Significant age-related changes in the magnitude of variance of facial shape were also observed (p < 0.05). Phenotypic growth trajectories representing developmental shape changes were similar in size (p > 0.05) between sexes but differed in direction (p < 0.05) in shape space and trajectory shape (p < 0.05). The magnitude of shape differences between sexes remained constant from 12 to 18 years. Results of frontal facial shape analyses after removing the effect of allometry were similar to results obtained before removal of allometry. For lateral facial configurations, allometric trajectories among the age-by-sex groups were similar in slope (p > 0.05) but varied in directions in the multidimensional shape space.ConclusionsOur findings suggested significant age-related changes in facial shape and provided a dynamic view of developmental changes in sexual dimorphism of facial shape. Allometry contributed minimally to developmental changes in frontal facial shape. In addition, the allometric trajectories for lateral facial configurations were similar in rate of shape change but differed in their directions in shape space.
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Project description:The impact of chromosomal inversions on human brain morphology remains underexplored. We studied 35 common inversions classified from genotypes of 33,018 adults with European ancestry. The inversions at 2p22.3, 16p11.2, and 17q21.31 reach genome-wide significance, followed by 8p23.1 and 6p21.33, in their association with cortical and subcortical morphology. The 17q21.31, 8p23.1, and 16p11.2 regions comprise the LRRC37, OR7E, and NPIP duplicated gene families. We find the 17q21.31 MAPT inversion region, known for harboring neurological risk, to be the most salient locus among common variants for shaping and patterning the cortex. Overall, we observe the inverted orientations decreasing brain size, with the exception that the 2p22.3 inversion is associated with increased subcortical volume and the 8p23.1 inversion is associated with increased motor cortex. These significant inversions are in the genomic hotspots of neuropsychiatric loci. Our findings are generalizable to 3,472 children and demonstrate inversions as essential genetic variation to understand human brain phenotypes.
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Project description:We aimed to clarify the changes in facial morphology of cats in relation to their interactions with humans. In Study 1, we compared the facial morphology of cats (feral mixed breed, owned domestic mixed breed, and owned domestic purebreds) with that of African wildcats. After collecting 3295 photos, we found that owned domestic cats' noses were significantly shorter than those of African wildcats and feral mixed breed, and there were no significant differences between the latter two. The eye angles were significantly more gradual in owned domestic purebreds than in the other groups. In Study 2, we examined the correlation between facial morphology and years with the owner, and found that the former is not affected by the latter. This suggests that changes in facial morphology are possibly transgenerational changes. The difference in facial morphology between wildcats and owned cats might be caused by domestication, and that between feral cats and owned cats might be due to feralization. In Study 3, we investigated whether cats' facial features affect cuteness ratings. We asked human participants to evaluate the cuteness of cats' face images and found that faces with shorter nose lengths were considered cuter. This suggests that owned domestic cats' facial morphology is preferred by humans.
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Project description:Tooth agenesis is a common structural birth defect in humans that results from failure of morphogenesis during early tooth development. The homeobox transcription factor Msx1 and the canonical Wnt signaling pathway are essential for "bud to cap" morphogenesis and are causal factors for tooth agenesis. Our recent study suggested that Msx1 regulates Wnt signaling during early tooth development by suppressing the expression of Dkk2 and Sfrp2 in the tooth bud mesenchyme, and it demonstrated partial rescue of Msx1-deficient molar teeth by a combination of DKK inhibition and genetic inactivation of SFRPs. In this study, we found that Sostdc1/Wise, another secreted Wnt antagonist, is involved in regulating the odontogenic pathway downstream of Msx1. Whereas Sostdc1 expression in the developing tooth germ was not increased in Msx1-/- embryos, genetic inactivation of Sostdc1 rescued maxillary molar, but not mandibular molar, morphogenesis in Msx1-/- mice with full penetrance. Since the Msx1-/-;Sostdc1-/- embryos exhibited ectopic Dkk2 expression in the developing dental mesenchyme, similar to Msx1-/- embryos, we generated and analyzed tooth development in Msx1-/-;Dkk2-/- double and Msx1-/-;Dkk2-/-;Sostdc1-/- triple mutant mice. The Msx1-/-;Dkk2-/- double mutants showed rescued maxillary molar morphogenesis at high penetrance, with a small percentage also exhibiting mandibular molars that transitioned to the cap stage. Furthermore, tooth development was rescued in the maxillary and mandibular molars, with full penetrance, in the Msx1-/-;Dkk2-/-;Sostdc1-/- mice. Together, these data reveal 1) that a key role of Msx1 in driving tooth development through the bud-to-cap transition is to control the expression of Dkk2 and 2) that modulation of Wnt signaling activity by Dkk2 and Sostdc1 plays a crucial role in the Msx1-dependent odontogenic pathway during early tooth morphogenesis.
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Project description:Canonical Wnt signaling plays an important role in development and disease, regulating transcription of target genes and stabilizing many proteins phosphorylated by Glycogen Synthase Kinase 3 (GSK3). We observed that the MiT family of transcription factors, which includes the melanoma oncogene MITF and the lysosomal master regulator TFEB, had the highest phylogenetic conservation of three consecutive putative GSK3 phosphorylation sites in animal proteomes. This prompted us to examine the relationship between MITF, endolysosomal biogenesis and Wnt signaling. Here we report that MITF expression levels correlated with the expression of a large subset of lysosomal genes in melanoma cell lines. MITF expression in the Tetracycline-inducible C32 melanoma model caused a marked increase in vesicular structures, and increased expression of late endosomal proteins such as Rab7, LAMP1, and CD63. These late endosomes were not functional lysosomes as they were less active in proteolysis, yet were able to concentrate Axin1, phospho-LRP6, phospho-β-Catenin, and GSK3 in the presence of Wnt ligands. This relocalization significantly enhanced Wnt signaling by increasing the number of multivesicular bodies (MVBs) into which the Wnt signalosome/destruction complex becomes localized upon Wnt signaling. We also show that the MITF protein was stabilized by Wnt signaling, through the novel C-terminal GSK3 phosphorylations identified here. MITF stabilization caused an increase in MVB biosynthesis, which in turn increased Wnt signaling, generating a positive feed-back loop that may function during the proliferative stages of melanoma. The results underscore the importance of misregulated endolysosomal biogenesis in Wnt signaling and cancer. Expression of selected Lysosomal genes and CLEAR element plus MITF were compared in 51 melanoma cell lines to a mixed reference pool containing equal amounts of 47 melanoma cell lines.
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Project description:Facial appearance expresses numerous cues about physical qualities as well as psychosocial and personality traits. Attractive faces are recognized clearly when seen and are often viewed advantageously in professional, social and romantic relationships. On the other hand, self-perceived attractiveness is not well understood and has been mainly attributed to psychological and cognitive factors. Here we use 3-dimensional facial surface data of a large young adult population (n = 601) to thoroughly assess the effect of facial shape on self-perceived facial attractiveness. Our results show that facial shape had a measurable effect on self-perception of facial attractiveness in both sexes. In females, self-perceived facial attractiveness was linked to decreased facial width, fuller anterior part of the lower facial third and more pronounced middle forehead and root of the nose. Males favored a well-defined chin, flatter cheeks and zygomas, and more pronounced eyebrow ridges, nose and middle forehead. The findings of this study support the notion that self-perceived facial attractiveness is not only motivated by psychological traits, but objectively measured phenotypic traits also contribute significantly. The role of social stereotypes for facial attractiveness in modern society is also inferred and discussed.
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Project description:Genetic-driven deregulation of the Wnt pathway is crucial but not sufficient for colorectal cancer (CRC) tumourigenesis. Here, we show that environmental glutamine restriction further augments Wnt signaling in APC mutant intestinal organoids to promote stemness and leads to adenocarcinoma formation in vivo via decreasing intracellular alpha-ketoglutarate (aKG) levels. aKG supplementation is sufficient to rescue low-glutamine induced stemness and Wnt hyperactivation. Mechanistically, we found that aKG promotes hypomethylation of DNA and histone H3K4me3, leading to an upregulation of differentiation-associated genes and downregulation of Wnt target genes, respectively. Using CRC patient-derived organoids and several in vivo CRC tumour models, we show that aKG supplementation suppresses Wnt signaling and promotes cellular differentiation, thereby significantly restricting tumour growth and extending survival. Together, our results reveal how metabolic microenvironment impacts Wnt signaling and identify aKG as a potent antineoplastic metabolite for potential differentiation therapy for CRC patients.
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Project description:Cholangiocarcinoma (CC) is typically diagnosed at an advanced stage and is refractory to surgical intervention and chemotherapy. Despite a global increase in the incidence of CC, little progress has been made toward the development of treatments for this cancer. Here we utilized human tissue; CC cell xenografts; a p53-deficient transgenic mouse model; and a non-transgenic, chemically induced rat model of CC that accurately reflects both the inflammatory and regenerative background associated with human CC pathology. Using these systems, we determined that the WNT pathway is highly activated in CCs and that inflammatory macrophages are required to establish this WNT-high state in vivo. Moreover, depletion of macrophages or inhibition of WNT signaling with one of two small molecule WNT inhibitors in mouse and rat CC models markedly reduced CC proliferation and increased apoptosis, resulting in tumor regression. Together, these results demonstrate that enhanced WNT signaling is a characteristic of CC and suggest that targeting WNT signaling pathways has potential as a therapeutic strategy for CC.
| S-EPMC4362247 | biostudies-literature
Project description:Wnt signaling has been implicated as a driver of prostate cancer-related osteoblast differentiation, and previous studies have linked modifications in Wnt function with the induction of tumor metastasis. A unique aspect of prostate cancer bone metastases in mouse models is their relative predilection to the hindlimb (femur) compared to the forelimb (humerus). Comparative gene expression profiling was performed within the humerus and femur from non-tumor-bearing mice to evaluate differences in the microenvironments of these locations. This revealed the relative overexpression of the Wnt signaling inhibitors WIF1 and SOST in the humerus compared to the femur, with increased WNT5A expression in femur bone marrow, suggesting a coordinated upregulation of Wnt signals within the femur compared to the humerus. Conditioned medium (CM) from bone marrow stromal cells (HS-5 cells) was used to mimic the bone marrow microenvironment, which strongly promoted prostate cancer cell invasion (3.3-fold increase in PC3 cells, P?<?.05; 7-fold increase in LNCaP cells, P?<?.05). WNT5A shRNA knockdown within the CM-producing HS-5 cells significantly decreased PC3 (56%, P?<?.05) and LNCaP (60%, P?<?.05) cell invasion. Similarly, preincubation of CM with WIF1 significantly blocked LNCaP cell invasion (40%, P?<?.05). shRNA-mediated knockdown of the Wnt receptors FZD4 and FZD8 also strongly inhibited tumor cell invasion (60% inhibition shFZD4, P?<?.05; 63% shFZD8, P?<?.05). Furthermore, small molecule inhibition of JNK, which is an important component of the noncanonical Wnt signaling pathway, significantly inhibited CM-mediated tumor invasion. Overall, this study reveals a role for Wnt signaling as a driver of prostate cancer bone metastatic tropism and invasion.
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