Biology subjects

Allan, K. C.

Publications and source records attributed to Allan, K. C..

5 recordsLinked to original sources

bioRxiv2023

Enteric glial hub cells coordinate intestinal motility

The enteric nervous system is a complex network of neurons and glia within the gut that coordinate gut motility. By optimizing single nucleus RNA-sequencing methods and spatial transcriptomics, we generated maps of the mouse duodenum and identified distinct molecular classes of enteric glia across the intestine with unique morphological and spatial identities. Here we show enteric glial functional specialization, with one myenteric subtype directly sensing force and expressing the mechanosensory ion channel PIEZO2. Genetic reduction of PIEZO2 in enteric glial populations enriched for this mechanosensory subtype led to defects in gastrointestinal motility. These results provide insight into the multifaceted functions of distinct enteric glial cell subtypes in maintaining gut health, and emphasize the importance of considering subtype-specific roles of enteric glia in a wide range of diseases and disorders.

neuroscience↗

bioRxiv2022

Cellular Maturation of Oligodendrocytes is Governed by Transient Gene Melting

Pluripotent stem cells (PSCs) provide an unlimited source for generating somatic cell types. However, generating fully mature cells constitutes a bottleneck for realizing their full potential in research and medicine. Here, we report a transcriptional mechanism that governs the timing of cellular maturation in post-mitotic oligodendrocytes. During differentiation of PSCs to oligodendrocytes, the transcription factor SOX6 redistributes from nearly all super enhancers in proliferating oligodendrocyte progenitor cells to cluster across specific gene bodies in immature oligodendrocytes. These sites exhibit gene melting, a process of extensive chromatin decondensation and transcription, which abruptly turns off upon maturation. Suppression of SOX6 deactivates these immaturity loci, resulting in rapid transition to mature myelinating oligodendrocytes. Cells harboring this immature oligodendrocyte SOX6 gene signature are specifically enriched in multiple sclerosis patient brains, suggestive that failed maturation may contribute to limited myelin regeneration in disease. Collectively, our finding that maturation rate is controlled by transient transcriptional clusters may inform approaches to accelerate the generation and regeneration of mature cell types. HIGHLIGHTSO_LITranscription factors (TFs) can act as gatekeepers of post-mitotic cellular maturation C_LIO_LIIn oligodendrocytes, clustering of SOX6 controls the immaturity program through transient gene melting C_LIO_LISuppressing SOX6 deactivates immaturity genes and unlocks oligodendrocyte maturation C_LIO_LISOX6 immaturity signature is enriched in oligodendrocytes in multiple sclerosis patients C_LI

developmental biology↗

bioRxiv2021

Chemical inhibition of pathological reactive astrocytes promotes neural protection

Disease, injury, and aging induce reactive astrocyte states with pathological functions1-4. In neurodegenerative diseases, inflammatory reactive astrocytes are abundant and contribute to progressive cell loss. Modulating the state or function of these reactive astrocytes thereby represents an attractive therapeutic goal5,6. Leveraging a cellular phenotypic screening platform, we show that chemical inhibitors of HDAC3 effectively block pathological astrocyte reactivity. Inhibition of HDAC3 reduces molecular and functional features of reactive astrocytes in vitro including inflammatory gene expression, cytokine secretion, and antigen presentation. Transcriptional and chromatin mapping studies show that HDAC3 inhibition mediates a switch between pro-inflammatory and anti-inflammatory states, which disarms the pathological functions of reactive astrocytes. Systemic administration of a blood-brain barrier penetrant chemical inhibitor of HDAC3, RGFP966, blocks reactive astrocyte formation and promotes axonal protection in vivo. Collectively, these results establish a platform for discovering chemical modulators of reactive astrocyte states, inform the mechanisms controlling astrocyte reactivity, and demonstrate the therapeutic potential of modulating astrocyte reactivity for neurodegenerative diseases.

neuroscience↗

bioRxiv2020

Non-Canonical Targets of HIF1a Drive Cell-Type-Specific Dysfunction

All mammalian cells sense and respond to insufficient oxygen, or hypoxia, through the activity of hypoxia-inducible factors (HIFs), an evolutionarily conserved family of transcriptional regulators that promote oxygen-independent energy metabolism and angiogenesis. While HIF activation is transiently protective for all cells, prolonged HIF activity drives distinct pathological responses in different tissues. How HIF achieves this pleiotropic effect is largely unknown. Here, we demonstrate that non-canonical targets of HIF1a impair the function of oligodendrocyte progenitor cells (OPCs) to generate oligodendrocytes. Beyond the canonical gene targets shared between all cell types, HIF1a also bound to and activated a unique set of targets in OPCs including Ascl2 and Dlx3. Each of these targets, when ectopically expressed, was sufficient to block oligodendrocyte development through suppression of the key oligodendrocyte regulator Sox10. Chemical screening revealed that inhibition of MEK/ERK signaling overcame the HIF1a-mediated block in oligodendrocyte generation by restoring Sox10 expression without impacting canonical HIF1a activity. Collectively this work defines the mechanism by which chronic HIF1a suppresses oligodendrocyte formation. More broadly, we establish that cell-type-specific HIF1a targets, independent of the canonical hypoxia response, perturb cell function and drive disease in chronic hypoxia.

developmental biology↗

bioRxiv2018

Therapeutic suppression of proteolipid protein rescues Pelizaeus-Merzbacher Disease in mice

Mutations in proteolipid protein 1 (PLP1) result in failure of myelination and severe neurological dysfunction in the X-linked pediatric leukodystrophy Pelizaeus-Merzbacher disease (PMD). The majority of PLP1 variants, including supernumerary copies and various point mutations, lead to early mortality. However, PLP1-null patients and mice display comparatively mild phenotypes, suggesting that reduction of aberrant PLP1 expression might provide a therapeutic strategy across PMD genotypes. Here we show, CRISPR-Cas9 mediated germline knockdown of Plp1 in the severe jimpy (Plp1jp) point mutation mouse model of PMD rescued myelinating oligodendrocytes, nerve conduction velocity, motor function, and lifespan to wild-type levels, thereby validating PLP1 suppression as a therapeutic approach. To evaluate the therapeutic potential of Plp1 suppression in postnatal PMD mice, we tested antisense oligonucleotides (ASOs) that stably decrease mouse Plp1 mRNA and protein in vivo. Administration of a single intraventricular dose of Plp1-targeted ASOs to postnatal jimpy mice increased myelination, improved motor behavior, and extended lifespan through an 8-month endpoint. Collectively, these results support the development of PLP1 suppression as a disease-modifying therapy for most PMD patients. More broadly, we demonstrate that RNA therapeutics can be delivered to oligodendrocytes in vivo to modulate neurological function and lifespan, opening a new treatment modality for myelin disorders.

neuroscience↗