Biology subjects

Rees, J. M.

Publications and source records attributed to Rees, J. M..

7 recordsLinked to original sources

bioRxiv2024

A pre-vertebrate endodermal origin of calcitonin-producing neuroendocrine cells

Vertebrate calcitonin-producing cells (C-cells) are neuroendocrine cells that secrete the small peptide hormone calcitonin in response to elevated blood calcium levels. C-cells are crucial for maintenance of calcium homeostasis, yet the embryonic and evolutionary origins of this cell type remain contentious. Whereas mouse C-cells reside within the thyroid gland and derive from pharyngeal endoderm, avian C-cells are located within ultimobranchial glands and were reported to derive from the neural crest. We use a comparative cell lineage tracing approach in a range of vertebrate model systems to resolve the ancestral embryonic origin of vertebrate C-cells. We find, contrary to previous studies, that chick C-cells derive from pharyngeal endoderm, with neural crest-derived cells instead contributing to connective tissue intimately associated with C-cells in the ultimobranchial gland. This endodermal origin of C-cells is conserved in a ray-finned bony fish (zebrafish) and a cartilaginous fish (the little skate, Leucoraja erinacea). Furthermore, we discover putative C-cell homologues within the endodermally-derived pharyngeal epithelium of the ascidian Ciona intestinalis and the amphioxus Branchiostoma lanceolatum, two invertebrate chordates that lack neural crest cells. Our findings point to a conserved endodermal origin of C-cells across vertebrates and to a pre-vertebrate origin of this cell type along the chordate stem.

developmental biology↗

bioRxiv2023

Fgf signalling is required for gill slit formation in the skate, Leucoraja erinacea

The gill slits of fishes develop from an iterative series of pharyngeal endodermal pouches that contact and fuse with surface ectoderm on either side of the embryonic head. We find in the skate (Leucoraja erinacea) that all gill slits form via a stereotypical sequence of epithelial interactions: 1) endodermal pouches approach overlying surface ectoderm, with 2) focal degradation of ectodermal basement membranes preceding endoderm-ectoderm contact; 3) endodermal pouches contact and intercalate with overlying surface ectoderm, and finally 4) perforation of a gill slit occurs by epithelial remodelling, without programmed cell death, at the site of endoderm- ectoderm intercalation. Skate embryos express Fgf8 and Fgf3 within developing pharyngeal epithelia during gill slit formation. When we inhibit Fgf signalling by treating skate embryos with the Fgf receptor inhibitor SU5402 we find that endodermal pouch formation, basement membrane degradation and endodermal-ectodermal intercalation are unaffected, but that epithelial remodelling and gill slit perforation fail to occur. These findings point to a role for Fgf signalling in epithelial remodelling during gill slit formation in the skate and, more broadly, to an ancestral role for Fgf signalling during pharyngeal pouch epithelial morphogenesis in vertebrate embryos.

developmental biology↗

bioRxiv2022

Wnt signalling, cell fate determination and anteroposterior polarity of the skate gill arch skeleton

The gill skeleton of cartilaginous fishes (sharks, skates, rays and holocephalans) exhibits a striking anterior-posterior polarity, with a series of fine appendages called branchial rays projecting from the posterior margin of the gill arch cartilages. We previously demonstrated in the skate (Leucoraja erinacea) that branchial rays derive from a posterior domain of pharyngeal arch mesenchyme that is responsive to Shh signalling from a distal gill arch epithelial ridge (GAER) signalling centre. However, how branchial ray progenitors are specified exclusively within posterior gill arch mesenchyme is not known. Here we show that genes encoding several Wnt ligands are expressed in the ectoderm immediately adjacent to the skate GAER, and that these Wnt signals are transduced largely in the anterior arch environment. Using pharmacological manipulation, we show that inhibition of Wnt signalling results in an anterior expansion of Shh signal transduction in developing skate gill arches, and in the formation of ectopic anterior branchial ray cartilages. Our findings demonstrate that ectodermal Wnt signalling contributes to gill arch skeletal polarity in skate by restricting Shh signal transduction and chondrogenesis to the posterior arch environment and highlights the importance of signalling interactions at embryonic tissue boundaries for cell fate determination in vertebrate pharyngeal arches.

developmental biology↗

bioRxiv2019

Physical activity reduces colorectal cancer risk independent of BMI - A two-sample Mendelian randomisation study

BackgroundEvidence from observational studies suggests a protective role for physical activity (PA) against colorectal cancer (CRC) risk. However, it has yet to be established a causal relationship. We conducted a two-sample Mendelian randomisation (MR) study to examine causality between physical activity and CRC risk.\n\nMethodsWe used common genetic variants associated with self-reported and accelerometer-based physical activity as instrumental variables (IVs) in this MR study. The IVs were derived from the largest available genome-wide association study (GWAS) of physical activity, namely UK Biobank. We analysed the effect of the IVs for physical activity in a large CRC GWAS that included 31 197 cases and 61 770 controls. We applied inverse variance weighted (IVW) method as the main analysis method.\n\nResultsOur results demonstrate a protective effect between accelerometer-based physical activity and CRC risk (the outlier-adjusted ORIVW was 0.92 per one standard deviation (SD) increase of accelerometer-base physical activity [95% CI: 0.87-0.98, P: 0.01]). The effect between self-reported physical activity and CRC risk was not statistically significant but was also supportive of an inverse association (the outlier-adjusted ORIVW was 0.61 per 1 SD increase of moderate-to-vigorous physical activity [95%CI: 0.36-1.06, P: 0.08]).\n\nConclusionsThe findings of this large MR study show for the first time that objectively measured physical activity is causally implicated in reducing CRC risk. The limitations of the study are that it is based on only two genetic instruments and that it has limited power, despite the study size. Nonetheless, at a population level, these findings provide strong reinforcing evidence to support public health policy measures that encourage exercise, even in obese individuals.

genetics↗

bioRxiv2019

Genetic determinants of lipids and cardiovascular disease outcomes: a wide-angled Mendelian randomization investigation

AimsTo systematically investigate causal relationships between circulating lipids and cardiovascular outcomes, using a Mendelian randomization approach.\n\nMethods and ResultsIn the primary analysis, we performed two-sample multivariable Mendelian randomization using data from participants of European ancestry. We also conducted univariable analyses using inverse-variance weighted and robust methods, and gene-specific analyses using variants that can be considered as proxies for specific lipid-lowering medications. We obtained associations with lipid fractions from the Global Lipids Genetics Consortium, a meta-analysis of 188,577 participants, and genetic associations with cardiovascular outcomes from 367,703 participants in UK Biobank.\n\nFor LDL-cholesterol, in addition to the expected positive associations with coronary artery disease (CAD) risk (odds ratio per 1 standard deviation increase [OR], 1.45; 95% confidence interval [95%CI] 1.35-1.57) and other atheromatous outcomes (ischemic cerebrovascular disease and peripheral vascular disease), we found independent associations of genetically-predicted LDL-cholesterol with abdominal aortic aneurysm (OR 1.75; 95%CI 1.40-2.17), and aortic valve stenosis (OR 1.46; 95%CI 1.25-1.70). Genetically-predicted triglyceride levels were positively associated with CAD (OR 1.25; 95%CI 1.12-1.40), aortic valve stenosis (OR 1.29; 95%CI 1.04-1.61), and hypertension (OR 1.17; 95%CI 1.07-1.27), but inversely associated with venous thromboembolism (OR 0.79; 95%CI 0.67-0.93). The positive associations of genetically-predicted LDL-cholesterol and triglycerides with heart failure and aortic stenosis appeared to be mediated by CAD.\n\nConclusionLowering LDL-cholesterol is likely to prevent abdominal aortic aneurysm and aortic stenosis, in addition to CAD and other atheromatous cardiovascular outcomes. Lowering triglycerides is likely to prevent CAD and aortic valve stenosis, but may increase risk of thromboembolism.

epidemiology↗

bioRxiv2019

Shared mechanisms between coronary heart disease and depression: findings from a large UK general population-based cohort

While comorbidity between coronary heart disease (CHD) and depression is evident, it is unclear whether the two diseases have shared underlying mechanisms. We performed a range of analyses in 367,703 unrelated middle-aged participants of European ancestry from UK Biobank, a population based cohort study, to assess whether comorbidity is primarily due to genetic or environmental factors, and to test whether cardiovascular risk factors and CHD are likely to be causally related to depression using Mendelian randomization. We showed family history of heart disease was associated with a 20% increase in depression risk (95% confidence interval [CI] 16% to 24%, p<0.0001), but a genetic risk score that is strongly associated with CHD risk was not associated with depression. An increase of one standard deviation in the CH D genetic risk score was associated with 71% higher CHD risk, but 1% higher depression risk (95% CI 0% to 3%; p=0.11). Mendelian randomization analyses suggested that triglycerides, interleukin-6 (IL-6), and C-reactive protein (CRP) are likely causal risk factors for depression. The odds ratio for depression per standard deviation increase in genetically-predicted triglycerides was 1.18 (95% CI 1.09 to 1.27; p=2x10-5); per unit increase in genetically-predicted log-transformed I L-6 was 0.74 (95% CI 0.62 to 0.89; p=0.0012); and per unit increase in genetically-predicted log-transformed CRP was 1.18 (95% CI 1.07 to 1.29; p=0.0009). Our analyses suggest that comorbidity between depression and CHD arises largely from shared environmental factors. I L-6, CRP and triglycerides, are likely to be causally linked with depression, so could be targets for treatment and prevention of depression.

genetics↗

bioRxiv2019

Factorial Mendelian randomization: using genetic variants to assess interactions

BackgroundFactorial Mendelian randomization is the use of genetic variants to answer questions about interactions. Although the approach has been used in applied investigations, little methodological advice is available on how to design or perform a factorial Mendelian randomization analysis. Previous analyses have employed a 2 x 2 approach, using dichotomized genetic scores to divide the population into 4 subgroups as in a factorial randomized trial. MethodsWe describe two distinct contexts for factorial Mendelian randomization: investigating interactions between risk factors, and investigating interactions between pharmacological interventions on risk factors. We propose two-stage least squares methods using all available genetic variants and their interactions as instrumental variables, and using continuous genetic scores as instrumental variables rather than dichotomized scores. We illustrate our methods using data from UK Biobank to investigate the interaction between body mass index and alcohol consumption on systolic blood pressure. ResultsSimulated and real data show that efficiency is maximized using the full set of interactions between genetic variants as instruments. In the applied example, between four- and ten-fold improvement in efficiency is demonstrated over the 2 x 2 approach. Analyses using continuous genetic scores are more efficient than those using dichotomized scores. Efficiency is improved by finding genetic variants that divide the population at a natural break in the distribution of the risk factor, or else divide the population into more equal sized groups. ConclusionsPrevious factorial Mendelian randomization analyses may have been under-powered. Efficiency can be improved by using all genetic variants and their interactions as instrumental variables, rather than the 2 x 2 approach. Key messagesO_LIFactorial Mendelian randomization is an extension of the Mendelian randomization paradigm to answer questions about interactions. C_LIO_LIThere are two contexts in which factorial Mendelian randomization can be used: for investigating interactions between risk factors, and interactions between pharmacological interventions on risk factors. C_LIO_LIWhile most applications of factorial Mendelian randomization have dichotomized the population as in a 2 x 2 factorial randomized trial, this approach is generally inefficient for detecting statistical interactions. C_LIO_LIIn the first context, efficiency is maximized by including all genetic variants and their cross-terms as instrumental variables for the two risk factors and their product term. C_LIO_LIIn the second context, efficiency is maximized by using continuous genetic scores rather than dichotomized scores. C_LI

epidemiology↗