Biology subjects

Foley, N.

Publications and source records attributed to Foley, N..

3 recordsLinked to original sources

bioRxiv2025

A 3D iPSC retina model reveals non-cell-autonomous and non-neuronal mechanism of photoreceptor degeneration in a lysosomal storage disorder.

Disruption of photoreceptor-retinal pigment epithelium (RPE) interface with loss of photoreceptor outer segments (POSs) in the retina is a pathological hallmark of several neurodegenerative and retinal diseases including lysosomal storage disorders like CLN3 disease. However, the retina is a functional composite in vivo; and in vitro stem cell models of retina that enable investigation of the photoreceptor-RPE interface in healthy and diseased retina are lacking. Here, we developed a 3D human pluripotent stem cell (hPSC)-derived retina model to investigate the photoreceptor-RPE interface in healthy and disease tissue. Using this 3D hPSC retina model, we demonstrated that the most common disease causing CLN3 mutation (CLN3{Delta}ex7-8) leads to reduced levels of acid ceramidase (AC) and consequently altered sphingolipid metabolism and signaling and POS loss in CLN3 disease. Consistent with the 3D hPSC retina model, altered sphingolipid metabolism and signaling coincided with POS loss in a large animal model of CLN3 disease, CLN3 miniswine. Therapeutically, recombinant human acid ceramidase (rhAC) targeted both altered sphingolipid metabolism and retina degeneration in the CLN3 hPSC retina model and the CLN3 miniswine eye. These findings demonstrate a proof-of-concept that rhAC can rescue disease phenotype in a large animal model of CLN3 disease and suggest that rhAC could be a therapeutic approach for CLN3 disease. One Sentence SummaryAcid ceramidase deficiency and consequently altered sphingolipid signaling promotes disease phenotype(s) in a lysosomal storage disorder, CLN3 disease.

neuroscience↗

bioRxiv2021

Phase Gradients and Anisotropy of the Suprachiasmatic Network

Biological neural networks operate at several levels of granularity, from the individual neuron to local neural circuits to networks of thousands of cells. The daily oscillation of the brains master clock in the suprachiasmatic nucleus (SCN) rests on a yet to be identified network of connectivity among its ~20,000 neurons. The SCN provides an accessible model to explore neural organization at several levels of organization. To relate cellular to local and global network behaviors, we explore network topology by examining SCN slices in three orientations using immunochemistry, light and confocal microscopy, real-time imaging, and mathematical modeling. Importantly, the results reveal small local groupings of neurons that form intermediate structures, here termed "phaseomes" which can be identified through stable local phase differences of varying magnitude among neighboring cells. These local differences in phase are distinct from the global phase relationship - that between individual cells and the mean oscillation of the overall SCN. The magnitude of the phaseomes local phase differences are associated with a global phase gradient observed in the SCNs rostral-caudal extent. Modeling results show that a gradient in connectivity strength can explain the observed gradient of phaseome strength, an extremely parsimonious explanation for the heterogeneous oscillatory structure of the SCN. Significance statementOscillation is a fundamental property of information sensing and encoding in the brain. Using real time imaging and modeling, we explore encoding of time by examining circadian oscillation in single neurons, small groups of neurons, and the entire nucleus, in the brains master: the suprachiasmatic nucleus (SCN). New insights into the network organization underlying circadian rhythmicity include the discovery of intermediate structures, termed phaseomes, characterized by neurons which are stably out of phase with their neighbors. Modeling indicates that the pattern of phaseomes across the tissue encompasses a gradient in connectivity strength from the rostral to caudal aspects of the nucleus. Anisotropy in network organization emerges from comparisons of phaseomes and connectivity gradients in sagittal, horizontal and coronal slices.

neuroscience↗

bioRxiv2019

Analysis of 19 Heliconiine Butterflies Shows Rapid TE-based Diversification and Multiple SINE Births and Deaths

Transposable elements (TEs) play major roles in the evolution of genome structure and function. However, because of their repetitive nature, they are difficult to annotate and discovering the specific roles they may play in a lineage can be a daunting task. Heliconiine butterflies are models for the study of multiple evolutionary processes including phenotype evolution and hybridization. We attempted to determine how TEs may play a role in the diversification of genomes within this clade by performing a detailed examination of TE content and accumulation in 19 species whose genomes were recently sequenced. We found that TE content has diverged substantially and rapidly in the time since several subclades shared a common ancestor with each lineage harboring a unique TE repertoire. Several novel SINE lineages have been established that are restricted to a subset of species. Furthermore, the previously described SINE, Metulj, appears to have gone extinct in two subclades while expanding to significant numbers in others. Finally, a burst of TE origination corresponds temporally to a burst of speciation in the clade, potentially providing support to hypotheses that TEs are drivers of genotypic and phenotypic diversification. This diversity in TE content and activity has the potential to impact how heliconiine butterflies continue to evolve and diverge.

evolutionary biology↗