Much of the basic information about individual organ development comes from studies using model species. Whereas conservation of gene regulatory networks across higher taxa supports generalizations ...made from a limited number of species, generality of mechanistic inferences remains to be tested in tissue culture systems. Here, using mammalian tooth explants cultured in isolation, we investigate self-regulation of patterning by comparing developing molars of the mouse, the model species of mammalian research, and the bank vole. A distinct patterning difference between the vole and the mouse molars is the alternate cusp offset present in the vole. Analyses of both species using 3D reconstructions of developing molars and jaws, computational modeling of cusp patterning, and tooth explants cultured with small braces show that correct cusp offset requires constraints on the lateral expansion of the developing tooth. Vole molars cultured without the braces lose their cusp offset, and mouse molars cultured with the braces develop a cusp offset. Our results suggest that cusp offset, which changes frequently in mammalian evolution, is more dependent on the 3D support of the developing jaw than other aspects of tooth shape. This jaw–tooth integration of a specific aspect of the tooth phenotype indicates that organs may outsource specific aspects of their morphology to be regulated by adjacent body parts or organs. Comparative studies of morphologically different species are needed to infer the principles of organogenesis.
The most mineralized tissue of the mammalian body is tooth enamel. Especially in species with thick enamel, three-dimensional (3D) tomography data has shown that the distribution of enamel varies ...across the occlusal surface of the tooth crown. Differences in enamel thickness among species and within the tooth crown have been used to examine taxonomic affiliations, life history, and functional properties of teeth. Before becoming fully mineralized, enamel matrix is secreted on the top of a dentine template, and it remains to be explored how matrix thickness is spatially regulated. To provide a predictive framework to examine enamel distribution, we introduce a computational model of enamel matrix secretion that maps the dentine topography to the enamel surface topography. Starting from empirical enamel-dentine junctions, enamel matrix deposition is modeled as a diffusion-limited free boundary problem. Using laboratory microCT and synchrotron tomographic data of pig molars that have markedly different dentine and enamel surface topographies, we show how diffusion-limited matrix deposition accounts for both the process of matrix secretion and the final enamel distribution. Simulations reveal how concave and convex dentine features have distinct effects on enamel surface, thereby explaining why the enamel surface is not a straightforward extrapolation of the dentine template. Human and orangutan molar simulations show that even subtle variation in dentine topography can be mapped to the enamel surface features. Mechanistic models of extracellular matrix deposition can be used to predict occlusal morphologies of teeth.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
When evolution leads to differences in body size, organs generally scale along. A well-known example of the tight relationship between organ and body size is the scaling of mammalian molar teeth. To ...investigate how teeth scale during development and evolution, we compared molar development from initiation through final size in the mouse and the rat. Whereas the linear dimensions of the rat molars are twice that of the mouse molars, their shapes are largely the same. Here, we focus on the first lower molars that are considered the most reliable dental proxy for size-related patterns due to their low within-species variability. We found that scaling of the molars starts early, and that the rat molar is patterned equally as fast but in a larger size than the mouse molar. Using transcriptomics, we discovered that a known regulator of body size, insulin-like growth factor 1 (
), is more highly expressed in the rat molars compared to the mouse molars. Ex vivo and in vivo mouse models demonstrated that modulation of the IGF pathway reproduces several aspects of the observed scaling process. Furthermore, analysis of IGF1-treated mouse molars and computational modeling indicate that IGF signaling scales teeth by simultaneously enhancing growth and by inhibiting the cusp-patterning program, thereby providing a relatively simple mechanism for scaling teeth during development and evolution. Finally, comparative data from shrews to elephants suggest that this scaling mechanism regulates the minimum tooth size possible, as well as the patterning potential of large teeth.
Tissue folds are structural motifs critical to organ function. In the intestine, bending of a flat epithelium into a periodic pattern of folds gives rise to villi, finger-like protrusions that enable ...nutrient absorption. However, the molecular and mechanical processes driving villus morphogenesis remain unclear. Here, we identify an active mechanical mechanism that simultaneously patterns and folds the intestinal epithelium to initiate villus formation. At the cellular level, we find that PDGFRA+ subepithelial mesenchymal cells generate myosin II-dependent forces sufficient to produce patterned curvature in neighboring tissue interfaces. This symmetry-breaking process requires altered cell and extracellular matrix interactions that are enabled by matrix metalloproteinase-mediated tissue fluidization. Computational models, together with in vitro and in vivo experiments, revealed that these cellular features manifest at the tissue level as differences in interfacial tensions that promote mesenchymal aggregation and interface bending through a process analogous to the active dewetting of a thin liquid film.
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•Mesenchymal aggregates generate forces that fold the mammalian intestinal epithelium•Active and fluid-like properties of aggregates program tissue geometry and pattern•Matrix metalloproteinases fluidize the subepithelial mesenchyme to initiate aggregation•Mesenchymal patterning conceptually resembles water dewetting from a hydrophobic surface
Subepithelial mesenchyme behaves like a dewetting fluid to pattern and fold the intestinal epithelium, initiating the formation of villi.
In metazoan tissues, cells decide their fates by sensing positional information provided by specialized morphogen proteins. To explore what features are sufficient for positional encoding, we asked ...whether arbitrary molecules (e.g., green fluorescent protein or mCherry) could be converted into synthetic morphogens. Synthetic morphogens expressed from a localized source formed a gradient when trapped by surface-anchoring proteins, and they could be sensed by synthetic receptors. Despite their simplicity, these morphogen systems yielded patterns reminiscent of those observed in vivo. Gradients could be reshaped by altering anchor density or by providing a source of competing inhibitor. Gradient interpretation could be altered by adding feedback loops or morphogen cascades to receiver cell response circuits. Orthogonal cell-cell communication systems provide insight into morphogen evolution and a platform for engineering tissues.
The patterning of repeated structures is a major theme in developmental biology, and the inter-relationship between spacing and size of such structures is an unresolved issue. Fungiform papillae are ...repeated epithelial structures that house taste buds on the anterior tongue. Here, we report that FGF signaling is a crucial regulator of fungiform papillae development. We found that mesenchymal FGF10 controls the size of the papillary area, while overall patterning remains unchanged. Our results show that FGF signaling negatively affects the extent of canonical Wnt signaling, which is the main activation pathway during fungiform papillae development; however, this effect does not occur at the level of gene transcription. Rather, our experimental data, together with computational modeling, indicate that FGF10 modulates the range of Wnt effects, likely via induction of
expression. We suggest that modification of the reach of Wnt signaling could be due to local changes in morphogen diffusion, representing a novel mechanism in this tissue context, and we propose that this phenomenon might be involved in a broader array of mammalian developmental processes.
An increasing number of mammalian species have been shown to have a history of hybridization and introgression based on genetic analyses. Only relatively few fossils, however, preserve genetic ...material, and morphology must be used to identify the species and determine whether morphologically intermediate fossils could represent hybrids. Because dental and cranial fossils are typically the key body parts studied in mammalian palaeontology, here we bracket the potential for phenotypically extreme hybridizations by examining uniquely preserved cranio-dental material of a captive hybrid between grey and ringed seals. We analysed how distinct these species are genetically and morphologically, how easy it is to identify the hybrids using morphology and whether comparable hybridizations happen in the wild. We show that the genetic distance between these species is more than twice the modern human-Neanderthal distance, but still within that of morphologically similar species pairs known to hybridize. By contrast, morphological and developmental analyses show grey and ringed seals to be highly disparate, and that the hybrid is a predictable intermediate. Genetic analyses of the parent populations reveal introgression in the wild, suggesting that grey-ringed seal hybridization is not limited to captivity. Taken together, we postulate that there is considerable potential for mammalian hybridization between phenotypically disparate taxa.
Prostate cancer (PCa) progression depends on androgen receptor activity. Cholesterol is required for biosynthesis of all steroid hormones, including androgens. Impact of cholesterol-lowering statins ...on androgens is unknown. We explored atorvastatin influence on serum and prostatic tissue steroidomic profiles (SP) to expose novel pathways for limiting androgen concentration in men with PCa.
This is a pre-planned post hoc analysis of ESTO-1 pilot randomised, double-blinded, clinical trial. Statin naïve men, scheduled for radical prostatectomy due to localised PCa, were randomised 1:1 to use daily 80 mg of atorvastatin or placebo before the surgery for a median of 28 days. Participants were recruited and treated at the Pirkanmaa Hospital District, Tampere, Finland. 108 of the 158 recruited men were included in the analysis based on sample availability for hormone profiling. Serum and prostatic tissue steroid profiles were determined using liquid chromatography mass spectrometry. Wilcoxon rank sum test and bootstrap confidence intervals (CI) were used to analyse the difference between placebo and atorvastatin arms.
Most serum and prostatic steroids, including testosterone and dihydrotestosterone, were not associated with atorvastatin use. However, atorvastatin use induced serum SP changes in 11-ketoandrostenedione (placebo 960pM, atorvastatin 617.5pM, p-value <0.0001, median difference -342.5; 95% CI -505.23 – -188.98). In the prostatic tissue, atorvastatin was associated with plausible downshift in 11- ketodihydrotestosterone (placebo 25.0pM in 100 mg tissue/1 mL saline, atorvastatin 18.5pM in 100 mg tissue/1 mL saline, p-value 0.027, median difference -6.53; 95% CI -12.8 – -0.29); however, this association diminished after adjusting for multiple testing. No serious harms were reported.
Atorvastatin was associated with adrenal androgen downshift in the serum and possibly in the prostate. The finding warrants further investigation whether atorvastatin could improve androgen deprivation therapy efficacy.
Funded by grants from the Finnish Cultural Foundation, Finnish Cancer Society, Academy of Finland, and the Expert Responsibility Area of the Tampere University Hospital.
NCT01821404.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The evolutionary relationships of extinct species are ascertained primarily through the analysis of morphological characters. Character inter-dependencies can have a substantial effect on ...evolutionary interpretations, but the developmental underpinnings of character inter-dependence remain obscure because experiments frequently do not provide detailed resolution of morphological characters. Here we show experimentally and computationally how gradual modification of development differentially affects characters in the mouse dentition. We found that intermediate phenotypes could be produced by gradually adding ectodysplasin A (EDA) protein in culture to tooth explants carrying a null mutation in the tooth-patterning gene Eda. By identifying development-based character inter-dependencies, we show how to predict morphological patterns of teeth among mammalian species. Finally, in vivo inhibition of sonic hedgehog signalling in Eda null teeth enabled us to reproduce characters deep in the rodent ancestry. Taken together, evolutionarily informative transitions can be experimentally reproduced, thereby providing development-based expectations for character-state transitions used in evolutionary studies.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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