Biology subjects

Morgan, K. J.

Publications and source records attributed to Morgan, K. J..

6 recordsLinked to original sources

bioRxiv2026

Mechanoresponsive modulation of nuclear pore complex structure and function by O-GlcNAc

Nuclear pore complexes (NPCs) control molecular exchange across the nuclear envelope, but how they tailor their selective permeability to meet the needs of specific cell types and/or environments remains poorly understood. We demonstrate that the strength of the NPC diffusion barrier differs across cell types, is particularly stringent in cultured neurons, and correlates with the O-linked N-acetylglucosamine (GlcNAc) modification of nucleoporins. Using conditional tools that specifically control nucleoporin GlcNAcylation, we show that GlcNAc modulates NPC permeability. Interestingly, nucleoporin GlcNAcylation is mechanosensitive, increasing in cells plated on stiff substrates, a condition where nuclear pores dilate. Indeed, we demonstrate that increasing or decreasing GlcNAcylation dilates and constricts NPCs, respectively. Further, O-linked N-acetylglucosamine transferase is recruited to modify NPCs upon their acute constriction during osmotic shock. Thus, cells employ GlcNAc to modulate steady-state NPC permeability in response to mechanical inputs and to counteract critical changes to their osmotic environment.

cell biology↗

bioRxiv2024

Visualizing nuclear pore complex plasticity with Pan-Expansion Microscopy

The exploration of cell-type and environmentally-responsive nuclear pore complex (NPC) plasticity requires new, accessible tools. Using pan-Expansion Microscopy (pan-ExM), NPCs were identified by machine learning-facilitated segmentation with resolved cytoplasmic rings (CR), inner rings (IR) and nuclear rings (NR). They exhibited a large range of diameters with a bias for dilated NPCs at the basal nuclear surface in clusters suggestive of local islands of nuclear envelope (NE) tension. Whereas hyperosmotic shock constricted NPCs analogously to those found in annulate lamellae (AL), depletion of LINC complexes specifically eliminated the modest nuclear surface diameter biases. Therefore, LINC complexes may contribute locally to nuclear envelope tension to toggle NPC diameter between dilated, but not constricted, states. Lastly, POM121 shifts from the NR to the IR specifically in induced pluripotent stem cell derived neurons (iPSNs) from a patient with C9orf72 amyotrophic lateral sclerosis (ALS). Thus, pan-ExM is a powerful tool to visualize NPC plasticity in physiological and pathological contexts at single NPC resolution. SummaryMorgan et al. demonstrate that pan-Expansion Microscopy is an exceptional tool for probing the molecular composition and structural plasticity of individual NPCs: they reveal LINC-complex dependent NPC diameter biases across the nuclear surface and changing nucleoporin positions in an ALS model.

cell biology↗

bioRxiv2023

Total infectome investigation of diphtheritic stomatitis in yellow-eyed penguins (Megadyptes antipodes) reveals a novel and abundant megrivirus

First identified in 2002, diphtheritic stomatitis (DS) is a devastating disease affecting yellow-eyed penguins (Megadyptes antipodes, or hoiho in te reo M[a]ori). The disease is associated with oral lesions in chicks and has caused significant morbidity and mortality. DS is widespread among yellow-eyed penguin chicks on mainland New Zealand yet appears to be absent from the subantarctic population. Corynebacterium spp. have previously been suspected as a causative agent yet, due to inconsistent cultures and inconclusive pathogenicity, its role in DS is unclear. Herein, we used a metatranscriptomic approach to identify potential causative agents of DS by revealing the presence and abundance of all viruses, bacteria, fungi and protozoa - together, the infectome. Oral and cloacal swab samples were collected from presymptomatic, symptomatic and recovered chicks along with a control group of healthy adults. Two novel viruses from the Picornaviridae were identified, one of which - yellow-eyed penguin megrivirus - was highly abundant in chicks irrespective of health status but not detected in healthy adults. Tissue from biopsied oral lesions also tested positive for the novel megrivirus upon PCR. We found no overall clustering among bacteria, protozoa and fungi communities at the genus level across samples, although Paraclostridium bifermentans was significantly more abundant in oral microbiota of symptomatic chicks compared to other groups. The detection of a novel and highly abundant megrivirus has sparked a new line of enquiry to investigate its potential association with DS.

microbiology↗

bioRxiv2022

A novel gyrovirus associated with a fatal respiratory disease in yellow-eyed penguin (Megadyptes antipodes) chicks

Yellow-eyed penguins (Megadyptes antipodes), or hoiho in te reo M[a]ori, are predicted to become extinct on mainland Aotearoa New Zealand in the next few decades, with infectious disease a significant contributor to their decline. A recent disease phenomenon termed respiratory distress syndrome (RDS) causing lung pathology has been identified in very young chicks. To date, no causative pathogens for RDS have been identified. In 2020 and 2021, the number of chick deaths from suspected RDS increased four- and five-fold, respectively, with a mortality rate of >90%. Here, we aimed to identify possible pathogens responsible for RDS disease impacting yelloweyed penguins. Total RNA was extracted from tissue samples collected during post-mortem of 43 chicks and subject to metatranscriptomic sequencing. From these data we identified a novel and highly abundant gyrovirus in 80% of tissue samples. This virus exhibited only 41% amino acid identity within VP1 to its closest relative, Gyrovirus 8, discovered in a diseased seabird. No other exogenous viral transcripts, nor pathogenic bacterial, protozoal and fungal organisms, were identified in these tissues. Due to the high relative abundance of viral reads, it is likely that this novel gyrovirus is associated with RDS in yellow-eyed penguin chicks. Author SummaryNew Zealands population of yellow-eyed penguins, also called hoiho, are predicted to become extinct in the next 20-30 years, with disease a major factor contributing to their decline. A new disease, causing fluid and bleeding into the lungs, was initially identified in 2019 in very young chicks. It was characterised as causing respiratory distress with a mortality of >90% usually within the first week of life. To date, no causative pathogens of the disease have been identified. We aimed to identify possible pathogens responsible for respiratory disease in these penguin chicks. A metatranscriptomic survey of dead chicks identified a novel and highly abundant gyrovirus present in diseased tissue, with closely related viruses causing disease in other avian hosts. It is, therefore, highly likely that this novel gyrovirus is associated with respiratory disease in these chicks. This finding offers the potential to increase the success of disease management in the critically endangered yellow-eyed penguin and possibly other at-risk penguin species. The potential to lessen mortality and slow the decline of the species is essential in protecting the biodiversity of New Zealands fauna and flora.

microbiology↗

bioRxiv2021

The minor spliceosome offers a therapeutically viable target for the treatment of a broad spectrum of cancers

Minor splicing is a second splicing system required for the correct expression of [~]700 human minor intron-containing genes (MIGs). Many MIGs are expressed in vigorously proliferating cells and are frequently dysregulated in cancer including BRAF, ERK, JNK and p38. Minor splicing is carried out by the minor spliceosome which comprises several unique components, including a 65kDa protein encoded by RNPC3. We show that Rnpc3 heterozygosity reduces tumour burden in a broad spectrum of in vivo cancer settings, without harming normal tissues. Using the collective power of zebrafish, mouse and human cancer models, we reveal a sequence of events connecting Rnpc3 deficiency and impaired splicing of MIGs to DNA damage and activation of a Tp53-dependent transcriptional program that restricts tumour burden by inducing cell cycle arrest and apoptosis. Interrogation of human liver and lung cancer transcriptomes curated in TCGA revealed that the expression of many of the genes encoding protein components of the minor spliceosome is upregulated in these cancers. This is accompanied by upregulation of the expression of MIGs that are enriched in cell cycle and DNA damage pathways. These findings suggest that cancer cells can invoke mechanisms to increase the efficiency of minor splicing to support their high proliferation rates. Finally, Kaplan Meier survival analysis shows that highly expressed MIGs are frequently associated with poor patient survival. Taken together, these results indicate that the minor spliceosome offers a therapeutically viable target for the treatment of a broad spectrum of cancers.

cancer biology↗

bioRxiv2021

Elys deficiency constrains Kras-driven tumour burden by amplifying oncogenic stress

The nucleoporin ELYS, encoded by AHCTF1, is a large multifunctional protein with essential roles in nuclear pore assembly and mitosis. Using a zebrafish model of hepatocellular carcinoma, in which the expression of an inducible mutant kras transgene (krasG12V) drives hepatocyte-specific hyperplasia and liver enlargement, we show that reducing ahctf1 gene dosage by 50% markedly shrinks tumour burden, while non-hyperplastic tissues are unaffected. We demonstrate that ahctf1 heterozygosity impairs nuclear pore formation, mitotic spindle assembly and chromosome segregation, leading to DNA damage and activation of TP53-dependent and independent mechanisms of cell death and cell cycle arrest. This selective vulnerability of cancer cells to mild disruption of Elys function uncovers a novel synthetic lethal interaction between ahctf1 and kras mutations that could be exploited therapeutically. Heterozygous expression of both ahctf1 and ranbp2, or treatment of heterozygous ahctf1 larvae with the nucleocytoplasmic transport inhibitor, Selinexor, completely blocked krasG12V-driven hepatocyte hyperplasia, revealing promising avenues for combinatorial treatments.

cancer biology↗