Microglia-Specific Expression of Olfml3 Is Directly Regulated by Transforming Growth Factor β1-Induced Smad2 Signaling

Neidert, Nicolas; Ehr, Alexander von; Zöller, Tanja; Spittau, Björn

doi:10.3389/fimmu.2018.01728

Cited by 30 publications

(34 citation statements)

References 28 publications

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“…Eleven genes were increased in expression exclusively in lobules III and VI of the Npc1 −/− mice (Supplementary Materials Table S2). The most significant increase in both lobules III and VI within Npc1 −/− mice was for Olfml3, which is a microglia lineage marker [42]. Additional microglia activation markers, including Lcp1 and Ctsb, were also included in the top five most significantly upregulated genes within lobules III and VI of the Npc1 −/− cerebellum [43,44].…”

Section: Differential Gene Expressionmentioning

confidence: 95%

Identification of Novel Pathways Associated with Patterned Cerebellar Purkinje Neuron Degeneration in Niemann-Pick Disease, Type C1

Martin

Williams

Cluzeau

et al. 2019

IJMS

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Niemann-Pick disease, type C1 (NPC1) is a lysosomal disease characterized by progressive cerebellar ataxia. In NPC1, a defect in cholesterol transport leads to endolysosomal storage of cholesterol and decreased cholesterol bioavailability. Purkinje neurons are sensitive to the loss of NPC1 function. However, degeneration of Purkinje neurons is not uniform. They are typically lost in an anterior-to-posterior gradient with neurons in lobule X being resistant to neurodegeneration. To gain mechanistic insight into factors that protect or potentiate Purkinje neuron loss, we compared RNA expression in cerebellar lobules III, VI, and X from control and mutant mice. An unexpected finding was that the gene expression differences between lobules III/VI and X were more pronounced than those observed between mutant and control mice. Functional analysis of genes with anterior to posterior gene expression differences revealed an enrichment of genes related to neuronal cell survival within the posterior cerebellum. This finding is consistent with the observation, in multiple diseases, that posterior Purkinje neurons are, in general, resistant to neurodegeneration. To our knowledge, this is the first study to evaluate anterior to posterior transcriptome-wide changes in gene expression in the cerebellum. Our data can be used to not only explore potential pathological mechanisms in NPC1, but also to further understand cerebellar biology.

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Section: Differential Gene Expressionmentioning

confidence: 95%

Identification of Novel Pathways Associated with Patterned Cerebellar Purkinje Neuron Degeneration in Niemann-Pick Disease, Type C1

Martin

Williams

Cluzeau

et al. 2019

IJMS

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“…There was no annotated SELPLG gene, or even an ambiguous ENSSSCG ID in Sscrofa11.1 whereas SELPLG was annotated with several alternative transcripts orthologous to the human gene on USMARCv1.0. OLFML3, another important marker of microglia in the mouse and human brain (Neidert et al, 2018) was not annotated on Sscrofa11.1 because it had been merged with the adjacent HIPK1 transcript, whereas it was correctly assigned on USMARCv1.0. Since downloading the data sets used in this analysis, further releases of Ensembl (Ensembl 97/98) have been made.…”

Section: A Resource and A Guide To Functional Annotationmentioning

confidence: 99%

Functional Annotation of the Transcriptome of the Pig, Sus scrofa, Based Upon Network Analysis of an RNAseq Transcriptional Atlas

Summers

Bush

et al. 2020

Front. Genet.

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The domestic pig (Sus scrofa) is both an economically important livestock species and a model for biomedical research. Two highly contiguous pig reference genomes have recently been released. To support functional annotation of the pig genomes and comparative analysis with large human transcriptomic data sets, we aimed to create a pig gene expression atlas. To achieve this objective, we extended a previous approach developed for the chicken. We downloaded RNAseq data sets from public repositories, down-sampled to a common depth, and quantified expression against a reference transcriptome using the mRNA quantitation tool, Kallisto. We then used the network analysis tool Graphia to identify clusters of transcripts that were coexpressed across the merged data set. Consistent with the principle of guilt-by-association, we identified coexpression clusters that were highly tissue or cell-type restricted and contained transcription factors that have previously been implicated in lineage determination. Other clusters were enriched for transcripts associated with biological processes, such as the cell cycle and oxidative phosphorylation. The same approach was used to identify coexpression clusters within RNAseq data from multiple individual liver and brain samples, highlighting cell type, process, and region-specific gene expression. Evidence of conserved expression can add confidence to assignment of orthology between pig and human genes. Many transcripts currently identified as novel genes with ENSSSCG or LOC IDs were found to be coexpressed with annotated neighbouring transcripts in the same orientation, indicating they may be products of the same transcriptional unit. The metaanalytic approach to utilising public RNAseq data is extendable to include new data sets and new species and provides a framework to support the Functional Annotation of Animals Genomes (FAANG) initiative.

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“…In addition, expression of OLFML3 is characteristic of microglia in humans (Butovsky et al 2014; Gosselin et al 2017) and mice (Figure S3; see also Neidert et al (2018) and data from Grabert et al (2016)), although it is not strongly expressed by other macrophage lineages. Genetic manipulation resulting in absence of microglia is associated with loss of Olfml3 expression in mice (R. Rojo et al , unpublished data).…”

Section: Discussionmentioning

confidence: 93%

Arginine to Glutamine Variant in Olfactomedin Like 3 (OLFML3) Is a Candidate for Severe Goniodysgenesis and Glaucoma in the Border Collie Dog Breed

Pugh

Farrell

Carlisle

et al. 2019

G3 Genes|Genomes|Genetics

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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.

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Microglia-Specific Expression of Olfml3 Is Directly Regulated by Transforming Growth Factor β1-Induced Smad2 Signaling

Cited by 30 publications

References 28 publications

Identification of Novel Pathways Associated with Patterned Cerebellar Purkinje Neuron Degeneration in Niemann-Pick Disease, Type C1

Identification of Novel Pathways Associated with Patterned Cerebellar Purkinje Neuron Degeneration in Niemann-Pick Disease, Type C1

Functional Annotation of the Transcriptome of the Pig, Sus scrofa, Based Upon Network Analysis of an RNAseq Transcriptional Atlas

Arginine to Glutamine Variant in Olfactomedin Like 3 (OLFML3) Is a Candidate for Severe Goniodysgenesis and Glaucoma in the Border Collie Dog Breed

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