Loss of cilia causes embryonic lung hypoplasia,liver fibrosis,and cholestasis in the talpid3 ciliopathy mutant

Sonic hedgehog plays an essential role in maintaining hepatoblasts in a proliferative non-differentiating state during embryogenesis. Transduction of the Hedgehog signaling pathway is dependent on the presence of functional primary cilia and hepatoblasts, therefore, must require primary cilia for normal function. In congenital syndromes in which cilia are absent or non-functional (ciliopathies) hepatorenal fibrocystic disease is common and primarily characterized by ductal plate malformations which underlie the formation of liver cysts, as well as less commonly, by hepatic fibrosis, although a role for abnormal Hedgehog signal transduction has not been implicated in these phenotypes. We have examined liver, lung and rib development in the talpid³ chicken mutant, a ciliopathy model in which abnormal Hedgehog signaling is well characterized. We find that the talpid³ phenotype closely models that of human short-rib polydactyly syndromes which are caused by the loss of cilia, and exhibit hypoplastic lungs and liver failure. Through an analysis of liver and lung development in the talpid³ chicken, we propose that cilia in the liver are essential for the transduction of Hedgehog signaling during hepatic development. The talpid³ chicken represents a useful resource in furthering our understanding of the pathology of ciliopathies beyond the treatment of thoracic insufficiency as well as generating insights into the role Hedgehog signaling in hepatic development.     

Intra-tooth stable isotope analysis of dentine: A step toward addressing selective mortality in the reconstruction of life history in the archaeological record

Intra-tooth stable isotope analysis of dentine provides a more sensitive means to examine infant and childhood life history in the past than conventional cross-sectional analyses that rely on age-at-death. In addition, reconstructions of early diet and life history using an intra-tooth approach circumvent potential problems associated with mortality bias, which may operate strongly during infancy and childhood. We present new intra-tooth stable carbon and nitrogen isotope profiles in dentine collagen of early forming permanent teeth in a sample of adults from the Medieval Nubian site of Kulubnarti. We interpret the profiles in terms of weaning behavior and dietary history, and we compare profiles generated from first molars and canines to explore the degree to which these tooth types correspond. We then compare the profiles to the occurrence of linear enamel hypoplasia to assess the relationship between the timing of the weaning process and stress events. Finally, we compare the longitudinal profiles to cross-sectional stable isotope data obtained from rib collagen to investigate how life histories might differ between those that survived into adulthood and those that did not. Results suggest that canine and first molar profiles are in broad agreement, that hypoplastic stress events occurred during rather than before or after the weaning process in our sample, and that survivors appear to have weaned earlier than the average non-survivor. We suggest that this approach may be useful for addressing the effects of selective mortality on reconstructions of early life history and the relationship between early life history and morbidity. Am J Phys Anthropol 155:281–293, 2014. © 2014 Wiley Periodicals, Inc.     

Technical note: Estimating original crown height in worn mandibular canines using aspects of dentin morphology

We present a novel method to estimate original crown height (OCH) for worn human mandibular canines using a cubic regression equation based on ratios of worn crown height and exposed dentin. This method may help alleviate issues frequently presented by worn teeth in dental analyses, including those in bioarchaeology. Mandibular canines (n = 28) from modern day New Zealand and English populations were selected. Crown height and dentin thickness were measured on dental thin sections (n = 19) and the resulting (log10) ratios were fitted to a cubic regression curve allowing OCH in worn crowns to be predicted. Variation in the dentin apex position was recorded and effects of angled wear slopes investigated allowing adjusted values to be generated. Our method is trialed for use on intact and sectioned teeth (n = 17). A cubic regression curve best describes the relationship between (log10) ratios and crown height deciles (R² = 0.996, df₁ = 3, df₂ = 336, p < 0.001). No significant differences were detected between OCH estimates using our method and digitally recreated cusp outlines of the same crowns (t = 1.024, df = 16, p > 0.05), with a mean absolute error of 0.171 mm and an adjusted coefficient of determination of 0.923. Our approach offers a quantitative method to estimate the percentage of OCH remaining on worn mandibular canines, and by extension, the OCH. Our estimates are comparable to digitally recreated cusps but less subjective and not limited to crowns with minimal wear.     

Branching morphogenesis of the ureteric epithelium during kidney development is coordinated by the opposing functions of GDNF and Sprouty1

Branching of ureteric bud-derived epithelial tubes is a key morphogenetic process that shapes development of the kidney. Glial cell line-derived neurotrophic factor (GDNF) initiates ureteric bud formation and promotes subsequent branching morphogenesis. Exactly how GDNF coordinates branching morphogenesis is unclear. Here we show that the absence of the receptor tyrosine kinase antagonist Sprouty1 (Spry1) results in irregular branching morphogenesis characterized by both increased number and size of ureteric bud tips. Deletion of Spry1 specifically in the epithelium is associated with increased epithelial Wnt11 expression as well as increased mesenchymal Gdnf expression. We propose that Spry1 regulates a Gdnf/Ret/Wnt11-positive feedback loop that coordinates mesenchymal-epithelial dialogue during branching morphogenesis. Genetic experiments indicate that the positive (GDNF) and inhibitory (Sprouty1) signals have to be finely balanced throughout renal development to prevent hypoplasia or cystic hyperplasia. Epithelial cysts develop in Spry1-deficient kidneys that share several molecular characteristics with those observed in human disease, suggesting that Spry1 null mice may be useful animal models for cystic hyperplasia.     

Brief communication: linear enamel hypoplasia and the shift from irregular to regular provisioning in Cayo Santiago rhesus monkeys (Macaca mulatta)

This study investigates changes in the prevalence of linear enamel hypoplasia (LEH) before and after the shift from irregular to regular provisioning in the Cayo Santiago rhesus monkey population. Prior to 1956, monkeys on this island colony did not receive consistent provisions, and were reported to be in poor health (Rawlins and Kessler [1986] The Cayo Santiago Macaques; Albany: State University of New York Press). A regular provisioning program, instituted in August 1956, resulted in the improved health of individuals and the growth of the population (Rawlins and Kessler [1986] The Cayo Santiago Macaques; Albany: State University of New York Press). LEH, a developmental defect of enamel, is a sensitive indicator of systemic physiological stress (Goodman and Rose [1990] Yrbk. Phys. Anthropol. 33:59-110). It was therefore hypothesized that the prevalence of LEH would be higher in monkeys who were irregularly provisioned than in monkeys who experienced regular provisioning. To test this hypothesis, teeth were examined for LEH in a sample of 181 female rhesus monkeys. The results support the hypothesis: the mean number of defects was statistically significantly higher in the preprovisioned group than it was in the postprovisioned one. When LEH prevalence was assessed using only defects occurring on antimeric pairs, the preprovisioned group again had a higher prevalence than the postprovisioned one, although the difference was not statistically significant, most likely because of the reduced sample size. The results of this study indicate that changes in LEH prevalence, at least in this population of rhesus monkeys, are associated with changes in nutritional status.     

Contact in the Andes: bioarchaeology of systemic stress in colonial Mórrope, Peru

The biocultural interchange between the Eastern and Western Hemispheres beginning in the late fifteenth century initiated an unprecedented adaptive transition for Native Americans. This article presents findings from the initial population biological study of contact in the Central Andes of Peru using human skeletal remains. We test the hypothesis that as a consequence of Spanish colonization, the indigenous Mochica population of Mórrope on the north coast of Peru experienced elevated systemic biological stress. Using multivariate statistical methods, we examine childhood stress reflected in the prevalence of linear enamel hypoplasias and porotic hyperostosis, femoral growth velocity, and terminal adult stature. Nonspecific periosteal infection prevalence and D(30+)/D(5+) ratio estimations of female fertility characterized adult systemic stress. Compared to the late pre-Hispanic population, statistically significant patterns of increased porotic hyperostosis and periosteal inflammation, subadult growth faltering, and depressed female fertility indicate elevated postcontact stress among both children and adults in Mórrope. Terminal adult stature was unchanged. A significant decrease in linear enamel hypoplasia prevalence may not indicate improved health, but reflect effects of high-mortality epidemic disease. Various lines of physiological, archaeological, and ethnohistoric evidence point to specific socioeconomic and microenvironmental factors that shaped these outcomes, but the effects of postcontact population aggregation in this colonial town likely played a fundamental role in increased morbidity. These results inform a model of postcontact coastal Andean health outcomes on local and regional scales and contribute to expanding understandings of the diversity of indigenous biological variation in the postcontact Western Hemisphere.     

Insights from the inside: histological analysis of abnormal enamel microstructure associated with hypoplastic enamel defects in human teeth

We studied the abnormalities in enamel microstructure associated with enamel hypoplasia in human teeth from the early medieval (5th-7th century AD) cemetery of Barbing, Germany, using light and scanning electron microscopy. The main aim of the study was to test the hypothesis that by analyzing the microstructure of fully formed enamel it is possible to reconstruct the reaction pattern of secretory ameloblasts to stress events leading to enamel hypoplasia. From the histological findings, a sequence of increasing impairment of secretory ameloblast function involving three thresholds was deduced. Surpassing of each of these thresholds is assumed to result in characteristic changes in enamel microstructure attributable to specific functional/morphological alterations of secretory ameloblasts. Based on our results we propose a model identifying the principal factors influencing the reaction of secretory ameloblasts to stress. The present study demonstrates that by including microscopic analysis in the study of enamel hypoplasia, it is possible to obtain a more complete picture of the formation of these developmental defects than is possible by inspection of crown surface features alone, and to draw more substantiated conclusions about the possible nature of developmental defects of enamel.     

Hypothesis for the causes and periodicity of repetitive linear enamel hypoplasia in large, wild African (Pan troglodytes and Gorilla gorilla) and Asian (Pongo pygmaeus) apes

Repetitive linear enamel hypoplasia (rLEH) is often observed in recent large-bodied apes from Africa and Asia as well as Mid- to Late Miocene sites from Spain to China. The ubiquity and periodicity of rLEH are not understood. Its potential as an ontogenetic marker of developmental stress in threatened species (as well as their ancient relatives) makes rLEH an important if enigmatic problem. We report research designed to show the periodicity of rLEH among West African Pan troglodytes (12 male, 32 female), Gorilla gorilla (10 male, 10 female), and Bornean and Sumatran Pongo pygmaeus (11 male, 9 female, 9 unknown) from collections in Europe. Two methods were employed. In the common chimpanzees and gorillas, the space between adjacent, macroscopically visible LEH grooves on teeth with two or more episodes was expressed as an absolute measure and as a ratio of complete unworn crown height. In the orangutans, the number of perikymata between episode onsets, as well as duration of rLEH, was determined from scanning electron micrographs of casts of incisors and canines. We conclude that stress in the form of LEH commences as early as 2.5 years of age in all taxa and lasts for several years, and even longer in orangutans; the stress is not chronic but episodic; the stressor has a strong tendency to occur in pulses of two occurrences each; and large apes from both land masses exhibit rLEH with an average periodicity of 6 months (or multiples thereof; Sumatran orangutans seem to show only annual stress), but this needs further research. This is supported by evidence of spacing between rLEH as well as perikymata counts. Duration of stress in orangutans averages about 6 weeks. Finally, the semiannual stressor transcends geographic and temporal boundaries, and is attributed to regular moisture cycles associated with the intertropical convergence zone modified by the monsoon. While seasonal cycles can influence both disease and nutritional stress, it is likely the combination of seasonal variation in fruiting cycles with specific stressors (malaria and/or intestinal parasites, especially hookworm) that results in this widespread phenomenon. This seasonal stress is sufficiently common and of long duration (6 weeks on average in orangutans) that we think rLEH may reflect significant stress in recent and, inferentially, fossil apes. Increasing seasonality may have impinged negatively on later Miocene apes, especially if they lacked a clear birth peak or seasonality in their reproductive cycles.