Biology subjects

Kim, R. D.

Publications and source records attributed to Kim, R. D..

4 recordsLinked to original sources

bioRxiv2023

Temporal and spatial analysis of astrocytes following stroke identifies novel drivers of reactivity

Astrocytes undergo robust gene expression changes in response to a variety of perturbations, including ischemic injury. How these transitions are affected by time, and how heterogeneous and spatially distinct various reactive astrocyte populations are, remain unclear. To address these questions, we performed spatial transcriptomics as well as single nucleus RNAseq of [~]138,000 mouse forebrain astrocytes at 1, 3, and 14 days after ischemic injury. We observed a widespread and temporally diverse response across many astrocyte subtypes. We identified astrocyte clusters unique in injury, including a transiently proliferative substate that may be BRCA1-dependent. We also found an interferon-responsive population that rapidly expands to the perilesion cortex at 1 day and persists up to 14 days post stroke. These lowly abundant, spatially restricted populations are likely functionally important in post-injury stabilization and resolution. These datasets offer valuable insights into injury-induced reactive astrocyte heterogeneity and can be used to guide functional interrogation of biologically meaningful reactive astrocyte substates to understand their pro- and anti-reparative functions following acute injuries such as stroke.

neuroscience↗

bioRxiv2023

Defining the molecular identity and morphology of glia limitans superficialis astrocytes in mouse and human

Astrocytes are a highly abundant glial cell type that perform critical homeostatic functions in the central nervous system. Like neurons, astrocytes have many discrete heterogenous subtypes. The subtype identity and functions are, at least in part, associated with their anatomical location and can be highly restricted to strategically important anatomical domains. Here, we report that astrocytes forming the glia limitans superficialis, the outermost border of brain and spinal cord, are a highly specialized astrocyte subtype and can be identified by a single marker: Myocilin (Myoc). We show that Myoc+ astrocytes cover the entire brain and spinal cord surface, exhibit an atypical morphology, and are evolutionarily conserved from rodents to humans. Identification of this highly specialized astrocyte subtype will advance our understanding of CNS homeostasis and potentially be targeted for therapeutic intervention to combat peripheral inflammatory effects on the CNS.

neuroscience↗

bioRxiv2022

INPP5D limits plaque formation and glial reactivity in the APP/PS1 mouse model of Alzheimer's disease

The dual specificity lipid/protein phosphatase SHIP1 (encoded by the INPP5D gene) is enriched in myeloid cells. Single nucleotide polymorphisms (SNPs) in INPP5D coding and non-coding regions impact risk for developing late onset sporadic Alzheimers disease (LOAD). We present pathological analyses with spatial transcriptomics of mice with tamoxifen-sensitive microglial knockdown of Inpp5d and show exacerbated plaque pathology, plaque-associated microglial density, and altered gene expression around plaques, suggesting novel markers for plaque-associated reactive microglia.

neuroscience↗

bioRxiv2021

Unique molecular features and cellular responses differentiate two populations of motor cortical layer 5b neurons in a preclinical model of ALS.

Many neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), lead to the selective degeneration of discrete cell types in the CNS despite the ubiquitous expression of many genes linked to disease. Therapeutic advancement depends on understanding unique cellular adaptations that underlie pathology of vulnerable cells in the context of disease-causing mutations. Here, we employ bacTRAP molecular profiling to elucidate cell type specific molecular responses of cortical upper motor neurons in a preclinical ALS model. Using two bacTRAP mouse lines that label distinct vulnerable or resilient projection neuron populations in motor cortex, we show that the regulation of oxidative phosphorylation (Oxphos) pathways is a common response in both cell types. However, differences in the baseline expression of genes involved in Oxphos and the handling of reactive oxygen species likely lead to the selective degeneration of the vulnerable cells. These results provide a framework to identify cell type-specific processes in neurodegenerative disease.

neuroscience↗