Biology subjects

Brown, S. D. M.

Publications and source records attributed to Brown, S. D. M..

4 recordsLinked to original sources

bioRxiv2024

DYRK1A kinase triplication is the major cause of Otitis Media in Down Syndrome

Down syndrome (DS), which arises from trisomy of the whole or part of chromosome 21 (Hsa21), is one of the most common genetic abnormalities in humans. DS manifests as a broad spectrum of phenotypic features, including hearing loss due to otitis media with effusion (OME), affecting around 50% of children with DS. We employed a panel of mouse models of DS comprising a nested series of duplications covering the regions of the mouse genome syntenic to Hsa21 in order to define the loci involved with OME in DS. We identified a major locus on mouse chromosome 16, containing only 12 genes, that causes OME. Within this region we demonstrate that normalizing the gene dosage of Dyrk1a restored the wild-type phenotype. Investigation of downstream pathways of DYRK1A uncovered a number of pathological mechanisms whereby DYRK1A triplication leads to middle ear inflammation and vascular leak. These include cross-talk of DYRK1A and TGF{beta} signaling and its impact on proinflammatory cytokines IL-6 and IL-17, as well as raised VEGF levels in the middle ear accompanied by increased Hif1a. We conclude that DYRK1A is a potential therapeutic target for OME in children with DS.

genetics↗

bioRxiv2024

CIB2 function is distinct from Whirlin in the development of cochlear stereocilia staircase pattern

Variations in genes coding for calcium and integrin binding protein 2 (CIB2) and whirlin cause deafness both in humans and mice. We previously reported that CIB2 binds to whirlin, and is essential for normal staircase architecture of auditory hair cells stereocilia. Here, we refine the interacting domains between these proteins and provide evidence that both proteins have distinct role in the development and organization of stereocilia bundles required for auditory transduction. Using a series of CIB2 and whirlin deletion constructs and nanoscale pulldown (NanoSPD) assays, we localized the regions of CIB2 that are critical for interaction with whirlin. AlphaFold 2 multimer, independently identified the same interacting regions between CIB2 and whirlin proteins, providing a detailed structural model of the interaction between the CIB2 EF2 domain and whirlin HHD2 domain. Next, we investigated genetic interaction between murine Cib2 and Whrn using genetic approaches. Hearing in mice double heterozygous for functionally null alleles (Cib2KO/+;Whrnwi/+) was similar to age-matched wild type mice, indicating that partial deficiency for both Cib2 and Whrn does not impair hearing. Double homozygous mutant mice (Cib2KO/KO;Whrnwi/wi) had profound hearing loss and cochlear stereocilia exhibited a predominant phenotype seen in single Whrnwi/wi mutants. Furthermore, over-expression of Whrn in Cib2KO/KOmice did not rescue the stereocilia morphology. These data suggest that, CIB2 is multifunctional, with key independent functions in development and/or maintenance of stereocilia staircase pattern in auditory hair cells.

neuroscience↗

bioRxiv2020

LAMA: Automated image analysis for developmentalphenotyping of mouse embryos

Advanced 3D imaging modalities such as micro computed tomography (micro-CT), high resolution episcopic microscopy (HREM), and optical projection tomography (OPT) have been readily incorporated into high-throughput phenotyping pipelines, such as the International Mouse Phenotyping Consortium (IMPC). Such modalities generate large volumes of raw data that cannot be immediately harnessed without significant resources of manpower and expertise. Thus, rapid automated analysis and annotation is critical to ensure that 3D imaging data is able to be integrated with other multi-dimensional phenotyping data. To this end, we present an automated computational mouse phenotyping pipeline called LAMA, based on image registration, which requires minimal technical expertise and human input to use. Designed predominantly for developmental biologists, our software performs image pre-processing, registration, statistical and gene function annotation, and segmentation of 3D micro-CT data. We address several limitations of current methods and create an easy to use, fast solution application for mouse embryo phenotyping. We also present a highly granular, novel anatomical E14.5 (14.5 days post coitus) atlas of a population average that integrates with our pipeline to allow a range of dysmorphologies to be automatically annotated as well as results from the validation of the pipeline.

bioinformatics↗

bioRxiv2019

A resource of targeted mutant mouse lines for 5,061 genes

The International Mouse Phenotyping Consortium reports the generation of new mouse mutant strains for over 5,000 genes from targeted embryonic stem cells on the C57BL/6N genetic background. This includes 2,850 null alleles for which no equivalent mutant mouse line exists, 2,987 novel conditional-ready alleles, and 4,433 novel reporter alleles. This nearly triples the number of genes with reporter alleles and almost doubles the number of conditional alleles available to the scientific community. When combined with more than 30 years of community effort, the total mutant allele mouse resource covers more than half of the genome. The extensively validated collection is archived and distributed through public repositories, facilitating availability to the worldwide biomedical research community, and expanding our understanding of gene function and human disease.

genetics↗