Biology subjects

Nott, A.

Publications and source records attributed to Nott, A..

3 recordsLinked to original sources

bioRxiv2020

Somatic mosaicism in the mature brain reveals clonal cellular distributions during cortical development

The structure of the human neocortex underlies species-specific features and is a reflection of intricate developmental programs. Here we analyzed neocortical cellular lineages through a comprehensive assessment of brain somatic mosaicism--which acts as a neutral recorder of lineage history. We employed deep whole genome and variant sequencing in a single postmortem neurotypical human brain across 25 anatomic regions and three distinct modalities: bulk geographies, sorted cell types, and single nuclei. We identified 259 mosaic variants, revealing remarkable differences in localization, clonal abundance, cell type specificity, and clade distribution. We identified a set of hierarchical cellular diffusion barriers, whereby the left-right axis separation of the neocortex occurs prior to anterior-posterior and dorsal-ventral axis separation. We also found that stochastic distribution is a driver of clonal dispersion, and that rules regarding cellular lineages and anatomical boundaries are often ignored. Our data provides a comprehensive analysis of brain somatic mosaicism across the human cerebral cortex, deconvolving clonal distributions and migration patterns in the human embryo. One Sentence SummaryComprehensive evaluation of brain somatic mosaicism in the adult human identifies rules governing cellular distribution during embryogenesis.

genomics↗

bioRxiv2020

Phosphoproteomics identifies microglial Siglec-F inflammatory response during neurodegeneration

Alzheimers disease (AD) is characterized by the appearance of amyloid-{beta} plaques, neurofibrillary tangles, and inflammation in brain regions involved in memory. Using mass spectrometry, we have quantified the phosphoproteome of the CK-p25, 5XFAD, and Tau P301S mouse models of neurodegeneration. We identified a shared response involving Siglec-F which was upregulated on a subset of reactive microglia. The human paralog Siglec-8 was also upregulated on microglia in AD. Siglec-F and Siglec-8 were upregulated following microglial activation with interferon gamma (IFN{gamma}) in BV-2 cell line and human stem-cell derived microglia models. Siglec-F overexpression activates an endocytic and pyroptotic inflammatory response in BV-2 cells, dependent on its sialic acid substrates and immunoreceptor tyrosine-based inhibition motif (ITIM) phosphorylation sites. Related human Siglecs induced a similar response in BV-2 cells. Collectively, our results point to an important role for mouse Siglec-F and human Siglec-8 in regulating microglial activation during neurodegeneration. HighlightsO_LIPhosphoproteomics analysis of CK-p25, 5XFAD, and Tau P301S mouse models finds dysregulated signaling networks associated with Alzheimers disease pathologies. C_LIO_LIA phosphorylation site on Siglec-F is found to be upregulated across all three models of disease. C_LIO_LIExpression of Siglec-F and its human paralog Siglec-8 is increased in reactive microglia. C_LIO_LIOverexpression of Siglec-F and Siglec-8 in vitro drives an endocytic and pyroptotic inflammatory response. C_LI In BriefPhosphoproteome signaling changes associated with Alzheimers disease (AD) are poorly characterized. Here, Morshed et al. apply phosphoproteomics to mouse models of AD to uncover a novel microglial receptor, Siglec-F, that is upregulated on a subset of inflammatory microglia across models of neurodegeneration. The human paralog, Siglec-8 is also found to be upregulated in late-onset AD microglia. Overexpression of Siglec-F and related human Siglecs activates pro-inflammatory signaling responses in BV-2 cells.

neuroscience↗

bioRxiv2019

Cell type-specific enhancer-promoter connectivity maps in the human brain and disease risk association

Unique cell type-specific patterns of activated enhancers can be leveraged to interpret non-coding genetic variation associated with complex traits and diseases such as neurological and psychiatric disorders. Here, we have defined active promoters and enhancers for major cell types of the human brain. Whereas psychiatric disorders were primarily associated with regulatory regions in neurons, idiopathic Alzheimers disease (AD) variants were largely confined to microglia enhancers. Interactome maps connecting GWAS variants in cell type-specific enhancers to gene promoters revealed an extended microglia gene network in AD. Deletion of a microglia-specific enhancer harboring AD-risk variants ablated BIN1 expression in microglia but not in neurons or astrocytes. These findings revise and expand the genes likely to be influenced by non-coding variants in AD and suggest the probable brain cell types in which they function.\n\nOne Sentence SummaryIdentification of cell type-specific regulatory elements in the human brain enables interpretation of non-coding GWAS risk variants.

neuroscience↗