ORCID Profile
0000-0001-9341-2562
Current Organisation
University of Oxford
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Publisher: Cold Spring Harbor Laboratory
Date: 25-07-2019
DOI: 10.1101/711127
Abstract: Goats ( Capra hircus ) are an economically important livestock species providing meat and milk across the globe. They are of particular importance in tropical agri-systems contributing to sustainable agriculture, alleviation of poverty, social cohesion and utilisation of marginal grazing. There are excellent genetic and genomic resources available for goats, including a highly contiguous reference genome (ARS1). However, gene expression information is limited in comparison to other ruminants. To support functional annotation of the genome and comparative transcriptomics we created a mini-atlas of gene expression for the domestic goat. RNA-Seq analysis of 22 transcriptionally rich tissues and cell-types detected the majority (90%) of predicted protein-coding transcripts and assigned informative gene names to more than 1000 previously unannotated protein-coding genes in the current reference genome for goat (ARS1). Using network-based cluster analysis we grouped genes according to their expression patterns and assigned those groups of co-expressed genes to specific cell populations or pathways. We describe clusters of genes expressed in the gastro-intestinal tract and provide the expression profiles across tissues of a subset of genes associated with functional traits. Comparative analysis of the goat atlas with the larger sheep gene expression atlas dataset revealed transcriptional differences between the two species in macrophage-associated signatures. The goat transcriptomic resource complements the large gene expression dataset we have generated for sheep and contributes to the available genomic resources for interpretation of the relationship between genotype and phenotype in small ruminants.
Publisher: Public Library of Science (PLoS)
Date: 08-10-2020
Publisher: Springer Science and Business Media LLC
Date: 15-02-2023
DOI: 10.1038/S41467-023-36606-W
Abstract: Following the diagnosis of a paediatric disorder caused by an apparently de novo mutation, a recurrence risk of 1–2% is frequently quoted due to the possibility of parental germline mosaicism but for any specific couple, this figure is usually incorrect. We present a systematic approach to providing in idualized recurrence risk. By combining locus-specific sequencing of multiple tissues to detect occult mosaicism with long-read sequencing to determine the parent-of-origin of the mutation, we show that we can stratify the majority of couples into one of seven discrete categories associated with substantially different risks to future offspring. Among 58 families with a single affected offspring (representing 59 de novo mutations in 49 genes), the recurrence risk for 35 (59%) was decreased below 0.1%, but increased owing to parental mixed mosaicism for 5 (9%)—that could be quantified in semen for paternal cases (recurrence risks of 5.6–12.1%). Implementation of this strategy offers the prospect of driving a major transformation in the practice of genetic counselling.
Publisher: Cold Spring Harbor Laboratory
Date: 14-04-2020
DOI: 10.1101/2020.04.14.040832
Abstract: C ylobacter is the leading cause of bacterial foodborne gastroenteritis in many countries. Source attribution studies unequivocally identify the handling or consumption of contaminated poultry meat as the primary risk factor. One potential strategy to control C ylobacter is to select poultry with increased resistance to colonisation. We conducted genomic and transcriptomic analyses of commercial pedigree broilers exposed to C ylobacter to examine persistent colonisation of the caecum as a quantitative trait. 3,000 broilers were genotyped using a 50K single nucleotide polymorphism (SNP) array and imputed to 600K SNPs. Genotypes were analysed for associations with the number of viable C ylobacter in the caeca. Heritability of the trait was modest but significantly greater than zero (h 2 =0.11 ± 0.03). Genome-wide association analyses confirmed quantitative trait loci (QTL) on chromosomes 14 and 16 previously identified using the progeny of crosses of inbred lines differing in resistance, and detected two additional genome-wide significant QTLs on chromosomes 19 and 26. RNA-Seq analysis of the transcriptome of caecal tonsils from birds at the low and high extremes of C. jejuni colonisation phenotype identified differentially transcribed genes, mainly located within the QTL on chromosome 16 and proximal to the major histocompatibility complex (MHC) locus. We also identified strong cis -QTLs located within the MHC suggesting the presence of cis -acting variation in both MHC class I, class II and BG genes. Multiple other cis- acting variants were identified in association with key immune genes ( COPS3, CCL4, CR1L, C4BP, PLGR ) in the other QTLs. Pathway and network analysis implicated cooperative functional pathways and networks in colonisation, including those related to antigen presentation, innate and adaptive immune responses, calcium, and renin-angiotensin signalling. While co-selection for enhanced resistance and other breeding goal traits is feasible, the frequency of resistance-associated alleles was high in the population studied and non-genetic factors significantly influence C ylobacter colonisation in poultry. C ylobacter infection is estimated to cause 95 million illnesses in people worldwide each year. Human infections mostly involve gastroenteritis, but can have severe complications. The handling or consumption of contaminated poultry meat is a key risk factor for human c ylobacteriosis. The bacteria reach high numbers in the intestines of chickens reared for meat (broilers) and are frequently found on carcasses after slaughter. Effective vaccines against C ylobacter are not yet available, and treatments to reduce carcass contamination (e.g. chlorination) are not acceptable in some markets. One alternative is to breed for chickens with improved resistance to C ylobacter colonisation. To test the feasibility of this option in commercial birds, we analysed the genetic make-up of 3,000 pedigree broilers and determined the number of C ylobacter in their gut. There were associations between specific regions of the chicken genome and resistance to C ylobacter . Within some of these regions, expression of certain genes differed between birds at the low and high extremes of C ylobacter colonisation, providing a potential explanation for genetic variation in resistance. Selection of poultry with increased resistance to C ylobacter colonisation may be a complementary strategy to improved biosecurity, management, handling and processing procedures to reduce the burden of C ylobacter on human health.
Publisher: Elsevier BV
Date: 09-2018
Publisher: Public Library of Science (PLoS)
Date: 03-06-2021
DOI: 10.1371/JOURNAL.PGEN.1009605
Abstract: Homozygous mutation of the Csf1r locus ( Csf1rko ) in mice, rats and humans leads to multiple postnatal developmental abnormalities. To enable analysis of the mechanisms underlying the phenotypic impacts of Csf1r mutation, we bred a rat Csf1rko allele to the inbred dark agouti (DA) genetic background and to a Csf1r -mApple reporter transgene. The Csf1rko led to almost complete loss of embryonic macrophages and ablation of most adult tissue macrophage populations. We extended previous analysis of the Csf1rko phenotype to early postnatal development to reveal impacts on musculoskeletal development and proliferation and morphogenesis in multiple organs. Expression profiling of 3-week old wild-type (WT) and Csf1rko livers identified 2760 differentially expressed genes associated with the loss of macrophages, severe hypoplasia, delayed hepatocyte maturation, disrupted lipid metabolism and the IGF1/IGF binding protein system. Older Csf1rko rats developed severe hepatic steatosis. Consistent with the developmental delay in the liver Csf1rko rats had greatly-reduced circulating IGF1. Transfer of WT bone marrow (BM) cells at weaning without conditioning repopulated resident macrophages in all organs, including microglia in the brain, and reversed the mutant phenotypes enabling long term survival and fertility. WT BM transfer restored osteoclasts, eliminated osteopetrosis, restored bone marrow cellularity and architecture and reversed granulocytosis and B cell deficiency. Csf1rko rats had an elevated circulating CSF1 concentration which was rapidly reduced to WT levels following BM transfer. However, CD43 hi non-classical monocytes, absent in the Csf1rko , were not rescued and bone marrow progenitors remained unresponsive to CSF1. The results demonstrate that the Csf1rko phenotype is autonomous to BM-derived cells and indicate that BM contains a progenitor of tissue macrophages distinct from hematopoietic stem cells. The model provides a unique system in which to define the pathways of development of resident tissue macrophages and their local and systemic roles in growth and organ maturation.
Publisher: The American Association of Immunologists
Date: 2018
DOI: 10.4049/IMMUNOHORIZONS.1700073
Abstract: Activated mouse macrophages metabolize arginine via NO synthase (NOS2) to produce NO as an antimicrobial effector. Published gene expression datasets provide little support for the activation of this pathway in human macrophages. Generation of NO requires the coordinated regulation of multiple genes. We have generated RNA-sequencing data from bone marrow–derived macrophages from representative rodent (rat), monogastric (pig and horse), and ruminant (sheep, goat, cattle, and water buffalo) species, and analyzed the expression of genes involved in arginine metabolism in response to stimulation with LPS. In rats, as in mice, LPS strongly induced Nos2, the arginine transporter Slc7a2, arginase 1 (Arg1), GTP cyclohydrolase (Gch1), and argininosuccinate synthase (Ass1). None of these responses was conserved across species. Only cattle and water buffalo showed substantial NOS2 induction. The species studied also differed in expression and regulation of arginase (ARG2, rather than ARG1), and amino acid transporters. Variation between species was associated with rapid promoter evolution. Differential induction of NOS2 and ARG2 between the ruminant species was associated with insertions of the Bov-A2 retrotransposon in the promoter region. Bov-A2 was shown to possess LPS-inducible enhancer activity in transfected RAW264.7 macrophages. Consistent with a function in innate immunity, NO production and arginine metabolism vary greatly between species and differences may contribute to pathogen host restriction.
Publisher: Oxford University Press (OUP)
Date: 02-2019
Abstract: One of the most significant physiological challenges to neonatal and juvenile ruminants is the development and establishment of the rumen. Using a subset of RNA-Seq data from our high-resolution atlas of gene expression in sheep (Ovis aries) we have provided the first comprehensive characterization of transcription of the entire gastrointestinal (GI) tract during the transition from pre-ruminant to ruminant. The dataset comprises 164 tissue s les from sheep at four different time points (birth, one week, 8 weeks and adult). Using network cluster analysis we illustrate how the complexity of the GI tract is reflected in tissue- and developmental stage-specific differences in gene expression. The most significant transcriptional differences between neonatal and adult sheep were observed in the rumen complex. Comparative analysis of gene expression in three GI tract tissues from age-matched sheep and goats revealed species-specific differences in genes involved in immunity and metabolism. This study improves our understanding of the transcriptomic mechanisms involved in the transition from pre-ruminant to ruminant by identifying key genes involved in immunity, microbe recognition and metabolism. The results form a basis for future studies linking gene expression with microbial colonization of the developing GI tract and provide a foundation to improve ruminant efficiency and productivity through identifying potential targets for novel therapeutics and gene editing.
Publisher: Cold Spring Harbor Laboratory
Date: 25-04-2019
DOI: 10.1101/619122
Abstract: Pervasive allelic variation at both gene and single nucleotide level (SNV) between in iduals is commonly associated with complex traits in humans and animals. Allele-specific expression (ASE) analysis, using RNA-Seq, can provide a detailed annotation of allelic imbalance and infer the existence of cis-acting transcriptional regulation. However, variant detection in RNA-Seq data is compromised by biased mapping of reads to the reference DNA sequence. In this manuscript we describe an unbiased standardised computational pipeline for allele-specific expression analysis using RNA-Seq data, which we have adapted and developed using tools available under open licence. The analysis pipeline we present is designed to minimise reference bias while providing accurate profiling of allele-specific expression across tissues and cell types. Using this methodology, we were able to profile pervasive allelic imbalance across tissues and cell types, at both the gene and SNV level, in Texel x Scottish Blackface sheep, using the sheep gene expression atlas dataset. ASE profiles were pervasive in each sheep and across all tissue types investigated. However, ASE profiles shared across tissues were limited and instead they tended to be highly tissue-specific. These tissue-specific ASE profiles may underlie the expression of economically important traits and could be utilized as weighted SNVs, for ex le, to improve the accuracy of genomic selection in breeding programmes for sheep. An additional benefit of the pipeline is that it does not require parental genotypes and can therefore be applied to other RNA-Seq datasets for livestock, including those available on the Functional Annotation of Animal Genomes (FAANG) data portal. This study is the first global characterisation of moderate to extreme ASE in tissues and cell types from sheep. We have applied a robust methodology for ASE profiling, to provide both a novel analysis of the multi-dimensional sheep gene expression atlas dataset, and a foundation for identifying the regulatory and expressed elements of the genome that are driving complex traits in livestock.
Publisher: Public Library of Science (PLoS)
Date: 25-11-2019
Publisher: Cold Spring Harbor Laboratory
Date: 05-2017
DOI: 10.1101/132696
Abstract: Sheep are a key source of meat, milk and fibre for the global livestock sector, and an important biomedical model. Global analysis of gene expression across multiple tissues has aided genome annotation and supported functional annotation of mammalian genes. We present a large-scale RNA-Seq dataset representing all the major organ systems from adult sheep and from several juvenile, neonatal and prenatal developmental time points. The Ovis aries reference genome (Oar v3.1) includes 27,504 genes (20,921 protein coding), of which 25,350 (19,921 protein coding) had detectable expression in at least one tissue in the sheep gene expression atlas dataset. Network-based cluster analysis of this dataset grouped genes according to their expression pattern. The principle of ‘guilt by association’ was used to infer the function of uncharacterised genes from their co-expression with genes of known function. We describe the overall transcriptional signatures present in the sheep gene expression atlas and assign those signatures, where possible, to specific cell populations or pathways. The findings are related to innate immunity by focusing on clusters with an immune signature, and to the advantages of cross-breeding by examining the patterns of genes exhibiting the greatest expression differences between purebred and crossbred animals. This high-resolution gene expression atlas for sheep is, to our knowledge, the largest transcriptomic dataset from any livestock species to date. It provides a resource to improve the annotation of the current reference genome for sheep, presenting a model transcriptome for ruminants and insight into gene, cell and tissue function at multiple developmental stages. Sheep are ruminant mammals kept as livestock for the production of meat, milk and wool in agricultural industries across the globe. Genetic and genomic information can be used to improve production traits such as disease resiliance. The sheep genome is however missing important information relating to gene function and many genes, which may be important for productivity, have no informative gene name. This can be remedied using RNA-Sequencing to generate a global expression profile of all protein-coding genes, across multiple organ systems and developmental stages. Clustering genes based on their expression profile across tissues and cells allows us to assign function to those genes. If for ex le a gene with no informative gene name is expressed in macrophages and is found within a cluster of known macrophage related genes it is likely to be involved in macrophage function and play a role in innate immunity. This information improves the quality of the reference genome and provides insight into biological processes underlying the complex traits that influence the productivity of sheep and other livestock species.
Publisher: Springer Science and Business Media LLC
Date: 07-08-2018
Publisher: Frontiers Media SA
Date: 10-2018
Publisher: Springer Science and Business Media LLC
Date: 13-06-2017
Publisher: Cold Spring Harbor Laboratory
Date: 03-04-2018
DOI: 10.1101/294504
Abstract: The phosphatidylserine receptor, TIM4, encoded by TIMD4 , mediates the phagocytic uptake of apoptotic cells. We applied anti-chicken TIM4 monoclonal antibodies, in combination with CSF1R reporter transgenes to dissect the function of TIM4 in chick ( Gallus gallus ). During development in ovo , TIM4 was present on the large majority of macrophages but expression became more heterogeneous post-hatch. Blood monocytes expressed KUL01, class II MHC and CSF1R- mApple uniformly. Around 50% of monocytes were positive for surface TIM4. They also expressed many other monocyte-specific transcripts at a higher level than TIM4 − monocytes. In liver, highly-phagocytic TIM4 hi cells shared many transcripts with mammalian Kupffer cells and were associated with uptake of apoptotic cells. Although they expressed CSF1R mRNA, Kupffer cells did not express the CSF1R -mApple transgene, suggesting that additional CSF1R transcriptional regulatory elements are required by these cells. By contrast, CSF1R -mApple was detected in liver TIM4 lo and TIM4 − cells which were not phagocytic and were more abundant than Kupffer cells. These cells expressed CSF1R, alongside high levels of FLT3 , MHCII, XCR1 and other markers associated with conventional dendritic cells (cDC) in mice. In bursa, TIM4 was present on the cell surface of two populations. Like Kupffer cells, bursal TIM4 hi phagocytes co-expressed many receptors involved in apoptotic cell recognition. TIM4 lo cells appear to be a sub-population of bursal B cells. In overview, TIM4 is associated with phagocytes that eliminate apoptotic cells in the chick. In the liver, TIM4 and CSF1R reporters distinguished Kupffer cells from an abundant population of DC-like cells.
Publisher: Cold Spring Harbor Laboratory
Date: 05-04-2018
DOI: 10.1101/295535
Abstract: The domestic chicken ( Gallus gallus ) is widely used as a model in developmental biology and is also an important livestock species. We describe a novel approach to data integration to generate an mRNA expression atlas for the chicken spanning major tissue types and developmental stages, using a erse range of publicly-archived RNA-seq datasets and new data derived from immune cells and tissues. Randomly down-s ling RNA-seq datasets to a common depth and quantifying expression against a reference transcriptome using the mRNA quantitation tool Kallisto ensured that disparate datasets explored comparable transcriptomic space. The network analysis tool Miru was used to extract clusters of co-expressed genes from the resulting expression atlas, many of which were tissue or cell-type restricted, contained transcription factors that have previously been implicated in their regulation, or were otherwise associated with biological processes, such as the cell cycle. The atlas provides a resource for the functional annotation of genes that currently have only a locus ID. We cross-referenced the RNA-seq atlas to a publicly available embryonic Cap Analysis of Gene Expression (CAGE) dataset to infer the developmental time course of organ systems, and to identify a signature of the expansion of tissue macrophage populations during development. Expression profiles obtained from public RNA-seq datasets – despite being generated by different laboratories using different methodologies – can be made comparable to each other. This meta-analytic approach to RNA-seq can be extended with new datasets from novel tissues, and is applicable to any species.
Publisher: Oxford University Press (OUP)
Date: 03-2019
Abstract: Goniodysgenesis is a developmental abnormality of the anterior chamber of the eye. It is generally considered to be congenital in dogs (Canis lupus familiaris), and has been associated with glaucoma and blindness. Goniodysgenesis and early-onset glaucoma initially emerged in Border Collies in Australia in the late 1990s and have subsequently been found in this breed in Europe and the USA. The objective of the present study was to determine the genetic basis of goniodysgenesis in Border Collies. Clinical diagnosis was based on results of examinations by veterinary ophthalmologists of affected and unaffected dogs from eleven different countries. Genotyping using the Illumina high density canine single nucleotide variant genotyping chip was used to identify a candidate genetic region. There was a highly significant peak of association over chromosome 17, with a p-value of 2 × 10−13. Expression profiles and evolutionary conservation of candidate genes were assessed using public databases. Whole genome sequences of three dogs with glaucoma, three severely affected by goniodysgenesis and three unaffected dogs identified a missense variant in the olfactomedin like 3 (OLFML3) gene in all six affected animals. This was homozygous for the risk allele in all nine cases with glaucoma and 12 of 14 other severely affected animals. Of 67 reportedly unaffected animals, only one was homozygous for this variant (offspring of parents both with goniodysgenesis who were also homozygous for the variant). Analysis of pedigree information was consistent with an autosomal recessive mode of inheritance for severe goniodysgenesis (potentially leading to glaucoma) in this breed. The identification of a candidate genetic region and putative causative variant will aid breeders to reduce the frequency of goniodysgenesis and the risk of glaucoma in the Border Collie population.
Publisher: Cold Spring Harbor Laboratory
Date: 07-07-2018
DOI: 10.1101/364752
Abstract: One of the most significant physiological challenges to neonatal and juvenile ruminants is the development and establishment of the rumen. Using a subset of RNA-Seq data from our high-resolution atlas of gene expression in sheep ( Ovis aries ) we have provided the first comprehensive characterisation of transcription of the entire the gastrointestinal (GI) tract during the transition from pre-ruminant to ruminant. The dataset comprises 168 tissue s les from sheep at four different time points (birth, one week, 8 weeks and adult). Using network cluster analysis we illustrate how the complexity of the GI tract is reflected in tissue- and developmental stage-specific differences in gene expression. The most significant transcriptional differences between neonatal and adult sheep were observed in the rumen complex. Differences in transcription between neonatal and adult sheep were particularly evident in macrophage specific signatures indicating they might be driving the observed developmental stage-specific differences. Comparative analysis of gene expression in three GI tract tissues from age-matched sheep and goats revealed species-specific differences in genes involved in immunity and metabolism. This study improves our understanding of the transcriptomic mechanisms involved in the transition from pre-ruminant to ruminant. It highlights key genes involved in immunity, microbe recognition, metabolism and cellular differentiation in the GI tract. The results form a basis for future studies linking gene expression with microbial colonisation of the developing GI tract and will contribute towards identifying genes that underlie immunity in early development, which could be utilised to improve ruminant efficiency and productivity. The raw RNA-Sequencing data are deposited in the European Nucleotide Archive (ENA) under study accessions PRJEB19199 (sheep) and PRJEB23196 (goat). Metadata for all s les is deposited in the EBI BioS les database under group identifiers SAMEG317052 (sheep) and SAMEG330351 (goat).
Publisher: Cold Spring Harbor Laboratory
Date: 14-03-2019
DOI: 10.1101/577015
Abstract: Milk yield is the most important dairy sheep trait and constitutes the key genetic improvement goal via selective breeding. Mastitis is one of the most prevalent diseases, significantly impacting on animal welfare, milk yield and quality, while incurring substantial costs. Our objectives were to determine the feasibility of a concomitant genetic improvement programme for enhanced milk production and resistance to mastitis. In idual records for milk yield and four mastitis-related traits were collected monthly throughout lactation for 609 ewes of the Chios breed. All ewes were genotyped with a mastitis specific custom-made 960 single nucleotide polymorphism array. We performed genomic association studies, (co)variance component estimation and pathway enrichment analysis, and characterised gene expression levels and the extent of allelic expression imbalance. Presence of heritable variation for milk yield was confirmed. There was no significant genetic correlation between milk yield and mastitis. Environmental factors appeared to favour both milk production and udder health. Four Quantitative Trait Loci (QTLs) affecting milk yield were detected on chromosomes 2, 12, 16 and 19, in locations distinct from those previously identified to affect mastitis resistance. Pathways, networks and functional gene clusters for milk yield were identified. Seven genes ( DNAJA1, DNAJC10, FGF10, GHR, HMGCS1, LYPLA1, OXCT1 ) located within the QTL regions were highly expressed in both the mammary gland and milk transcriptome, suggesting involvement in milk synthesis and production. Furthermore, the expression of four genes ( DNAJC10, FGF10, OXCT1, EMB ) was enriched in immune tissues implying a favourable pleiotropic effect or likely role in milk production during udder infection. In conclusion, the absence of genetic antagonism between milk yield and mastitis resistance suggests that simultaneous genetic improvement of both traits be achievable. The detection of milk yield QTLs with the mastitis array underpins the latter’s utility as a breeding tool for the genetic enhancement of both traits.
Publisher: Public Library of Science (PLoS)
Date: 15-09-2017
Publisher: Frontiers Media SA
Date: 24-07-2019
Publisher: Springer Science and Business Media LLC
Date: 24-04-2018
Publisher: The American Association of Immunologists
Date: 15-02-2019
Abstract: The phosphatidylserine receptor TIM4, encoded by TIMD4, mediates the phagocytic uptake of apoptotic cells. We applied anti-chicken TIM4 mAbs in combination with CSF1R reporter transgenes to dissect the function of TIM4 in the chick (Gallus gallus). During development in ovo, TIM4 was present on the large majority of macrophages, but expression became more heterogeneous posthatch. Blood monocytes expressed KUL01, class II MHC, and CSF1R-mApple uniformly. Around 50% of monocytes were positive for surface TIM4. They also expressed many other monocyte-specific transcripts at a higher level than TIM4− monocytes. In liver, highly phagocytic TIM4hi cells shared many transcripts with mammalian Kupffer cells and were associated with uptake of apoptotic cells. Although they expressed CSF1R mRNA, Kupffer cells did not express the CSF1R-mApple transgene, suggesting that additional CSF1R transcriptional regulatory elements are required by these cells. By contrast, CSF1R-mApple was detected in liver TIM4lo and TIM4− cells, which were not phagocytic and were more abundant than Kupffer cells. These cells expressed CSF1R alongside high levels of FLT3, MHCII, XCR1, and other markers associated with conventional dendritic cells in mice. In bursa, TIM4 was present on the cell surface of two populations. Like Kupffer cells, bursal TIM4hi phagocytes coexpressed many receptors involved in apoptotic cell recognition. TIM4lo cells appear to be a subpopulation of bursal B cells. In overview, TIM4 is associated with phagocytes that eliminate apoptotic cells in the chick. In the liver, TIM4 and CSF1R reporters distinguished Kupffer cells from an abundant population of dendritic cell–like cells.
Publisher: Springer Science and Business Media LLC
Date: 16-08-2017
Publisher: The American Association of Immunologists
Date: 11-2018
Abstract: We have produced Csf1r-deficient rats by homologous recombination in embryonic stem cells. Consistent with the role of Csf1r in macrophage differentiation, there was a loss of peripheral blood monocytes, microglia in the brain, epidermal Langerhans cells, splenic marginal zone macrophages, bone-associated macrophages and osteoclasts, and peritoneal macrophages. Macrophages of splenic red pulp, liver, lung, and gut were less affected. The pleiotropic impacts of the loss of macrophages on development of multiple organ systems in rats were distinct from those reported in mice. Csf1r−/− rats survived well into adulthood with postnatal growth retardation, distinct skeletal and bone marrow abnormalities, infertility, and loss of visceral adipose tissue. Gene expression analysis in spleen revealed selective loss of transcripts associated with the marginal zone and, in brain regions, the loss of known and candidate novel microglia-associated transcripts. Despite the complete absence of microglia, there was little overt phenotype in brain, aside from reduced myelination and increased expression of dopamine receptor-associated transcripts in striatum. The results highlight the redundant and nonredundant functions of CSF1R signaling and of macrophages in development, organogenesis, and homeostasis.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Stephen Bush.