Biology subjects

McCracken, S.

Publications and source records attributed to McCracken, S..

4 recordsLinked to original sources

bioRxiv2026

Differential Survival of Retinal Ganglion Cell Types Following Branch Retinal Vein Occlusion

Background. Branch retinal vein occlusion (BRVO) is a common cause of retinal ischemia, rapidly inducing neuronal death and often producing irreversible vison loss. Interventions such as thrombolysis restore perfusion but cannot recover neurons already lost, and most patients retain permanent visual deficits. Identifying which neuronal populations die, and how rapidly, may therefore reveal timing windows and targets for neuroprotective treatment. Aims. To determine the timing of pathology, we evaluated vascular changes and neuronal degeneration in a photocoagulation-induced mouse model of BRVO. To determine differences in retinal ganglion cells (RGC) type susceptibility, we tracked the survival of RGC subpopulations using immunofluorescence markers. Methods. BRVO was induced by retro-orbital injection of Rose Bengal and FITC dextran followed by targeted photocoagulation of a branch vein. Obstruction was confirmed by fluorescein angiography and vascular damage was viewed by optical coherence tomography angiography. Cell survival was quantified by immunostaining at 3, 7, and 14 days using RNA Binding Protein with Multiple Splicing (RBPMS, pan RGC). RGC subtype markers for intrinsically photosensitive RGCs (TBR2), RGCs (SPP1), ON OFF direction-selective RGCs (CART), and F RGCs (FOXP2) were used to examine differences in survival across RGC types. Results. Occlusion selectively disrupted the superficial and intermediate capillary plexus, sparing the deep plexuses. All examined neuronal populations were significantly depleted, but with markedly different magnitude and timing. RGCs and F RGCs were the most vulnerable subtypes, both approaching complete loss by one week, whereas intrinsically photosensitive RGCs were the most resistant. Conclusion. RGCs, typically resilient in glaucoma, trauma, and excitotoxicity, were markedly vulnerable in BRVO, indicating that RGC subtype susceptibility is insult-specific.

neuroscience↗

bioRxiv2026

A paradoxical relationship between mitochondrial calcium regulation and retinal ganglion cell degeneration after axon damage

Retinal ganglion cells (RGCs) degenerate in optic neuropathies like glaucoma and traumatic optic nerve injury leading to irreversible vision loss. Higher levels of homeostatic Ca2+ and canonical Ca2+ regulated signaling promote RGC survival in animal models of glaucoma and optic nerve injury. Mitochondrial dysfunction is also a hallmark of degenerating neurons, including RGCs. Here, we investigate the intersection of mitochondrial function, Ca2+ homeostasis, and cellular resilience by performing an optic nerve crush model of RGC degeneration while monitoring and manipulating mitochondrial Ca2+ levels (mito-Ca2+). We find that mito-Ca2+ is predicative of RGC survival in that surviving RGCs are enriched for higher homeostatic mito-Ca2+ levels. Mitochondrial dysfunction was observed where mito-Ca2+ was reduced in RGCs after injury, regardless of survival. We then examined the importance of higher mito-Ca2+ in surviving RGCs by altering mito-Ca2+ levels and Ca2+ transit using pharmacological and AAV-mediated approaches. Paradoxically, treatment to decrease mito-Ca2+ increased survival to ONC. We then manipulated mito-Ca2+ permeability by altering the expression levels of the mitochondrial calcium uniporter (MCU) pore forming subunit that allows Ca2+ to enter mitochondria from the cytoplasm. Overexpressing MCU reduced RGC survival to injury, while shRNA knockdown of MCU increased RGC survival. These results reveal a complex relationship between mito-Ca2+ and RGC degeneration and suggest that well-surviving RGCs may be under chronic mitochondrial stress due to higher homeostatic mito-Ca2+ levels.

neuroscience↗

bioRxiv2025

The Androgen Receptor and MYC synergise to modulate the synthesis of Siglec-7 ligands in prostate cancer

Glyco-immune checkpoints have recently been shown to be critical mediators of immunotherapy resistance across multiple cancer types. In clinical trials, immunotherapeutic treatments for prostate cancer have failed to elicit durable clinical responses. PCa progression is driven by transcriptional networks regulated by key transcription factors including the androgen receptor (AR) and the oncogene MYC. How this crossover between hormone and oncogene-driven signalling pathways regulates tumour glyco-immune checkpoints remains unclear. Here, we show that O-glycans are the major substrates for sialylation in prostate cancer and that sialyltransferases that have preferences for O-glycans are differentially regulated by androgens. We show that supraphysiological levels of androgens produce distinct glycopeptide profiles in prostate cancer cells compared with cells exposed to physiological androgens. Additionally, we identify a direct and coordinated role for AR and MYC in regulating ST3Gal1 and the synthesis of Siglec-7 ligands in prostate cancer. Both transcription factors converge to repress ST3GAL1, thereby limiting the generation of Siglec-7 ligands. These findings highlight a context-dependent, cooperative relationship between the AR and MYC in shaping the tumour sialome, linking hormonal signalling and oncogenic transcription to Siglec biology. Our study highlights how cell-type specific differences in transcriptional networks has important downstream effects for immune modulating glycans and has tumour specific clinical implications.

cancer biology↗

bioRxiv2024

Mistargeted retinal axons form synaptically segregated subcircuits in the visual thalamus of albino mice

In albino mice and EphB1 knock out mice, mistargeted retinal ganglion cell (RGC) axons form dense islands of axon terminals in the dorsal lateral geniculate nuclei (dLGN). The formation of these islands of retinal input depends on developmental patterns of spontaneous retinal activity. We reconstructed the microcircuitry of the activity dependent islands and found that the boundaries of the island represent a remarkably strong segregation within retinogeniculate connectivity. We conclude that, when sets of retinal input are established in the wrong part of the dLGN, the developing circuitry responds by forming a synaptically isolated subcircuit within the otherwise fully connected network. The fact that there is a developmental starting condition that can induce a synaptically segregated microcircuit has important implications for our understanding of the organization of visual circuits and for our understanding of the implementation of activity dependent development.

neuroscience↗