Biology subjects

Yu-Wai-Man, P.

Publications and source records attributed to Yu-Wai-Man, P..

4 recordsLinked to original sources

bioRxiv2026

An NR2F1-dependent retinoic acid network controls retinal specialization in mice and reveals foveal hypoplasia in patients with BBSOAS

The molecular programs that establish specialized retinal regions during development are essential for high-acuity vision, yet how their disruption contributes to human visual disorders remains poorly understood. Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS), caused by pathogenic variants in NR2F1 and characterized by visual impairment, provides an opportunity to investigate these mechanisms. Using single-cell RNA sequencing of three complementary Nr2f1 mouse models, including two carrying patient-specific mutations, we identified a shared Nr2f1-dependent transcriptional program enriched in retinoic acid (RA) pathway genes. Loss or mutation of Nr2f1 disrupted the spatial organization of RA signaling, most prominently by expanding the dorso-equatorial Cyp26a1 expression domain into ventral retina and reducing ventral determinants such as Vax2. These molecular changes were associated with altered dorso-ventral distribution of S- and M-opsin-expressing cone photoreceptors. We further demonstrate that human NR2F1 binds a conserved regulatory region upstream of CYP26A1, supporting its direct role in regulating local RA availability. Finally, high-resolution optical coherence tomography in individuals with BBSOAS revealed reproducible foveal abnormalities, including a smaller and shallower foveal pit and increased central retinal thickness, consistent with foveal hypoplasia. These findings uncover a previously unrecognized retina-intrinsic component of BBSOAS visual pathology and establish an NR2F1-RA/CYP26A1 regulatory axis linking developmental retinal regionalization to human foveal specialization.

developmental biology↗

bioRxiv2024

An fMRI-based Approach for Measuring Contrast Sensitivity Across the Visual Field in Visual Cortex

Peripheral vision is crucial for daily activities and quality of life, yet traditional measures of visual function like visual acuity primarily assess central vision. Visual field tests can evaluate peripheral vision but require extended focus combined with precise fixation, often very challenging for patients with severe sight loss. Functional MRI (fMRI) with population receptive field (pRF) mapping offers a non-invasive way to map scotomas but is limited by its reliance on single contrast levels and the necessity of accurate fixation. We developed an fMRI-based approach to measure contrast sensitivity across the visual field without the need for precise fixation. By combining large-field stimulation with varying spatial frequencies and contrast levels with either pRF mapping or a retinotopic atlas based on anatomical landmarks, we modeled contrast sensitivity in the primary visual cortex (V1) over a large (40 deg) expanse of the visual field. In seven normal-sighted participants, we characterized differences in V1 cortical sensitivity across eccentricities and visual quadrants, finding reliable and reproducible patterns of sensitivity differences at individual and session levels. To assess the methods tolerance to fixation variability, we further investigated how different levels of eye movement affect cortical sensitivity patterns in two participants. We found that cortical sensitivity patterns were largely preserved across eye movement, particularly at low spatial frequencies. This suggests that our approach can accommodate several degrees of fixation instability, making it suitable for populations with unstable or biased fixation for whom visual field maps are harder to acquire behaviorally (e.g., patients with dense central scotoma or strabismus). Additionally, our method effectively visualized cases of simulated and disease-linked sensitivity loss at the cortical level. Crucially, we demonstrated that these results could be largely recovered using a structure-based retinotopic atlas, eliminating the need for pRF mapping and precise fixation - although such an approach reduced sensitivity. This approach, integrating large-field stimulation with a retinotopic atlas, offers a promising tool for monitoring vision loss and recovery in patients with various visual impairments, addressing a significant challenge in current clinical assessments.

neuroscience↗

bioRxiv2024

Multiomic Screening Unravels the Immunometabolic Signatures and Drug Targets of Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is a significant cause of visual impairment in the aging population, with the pathophysiology driven by a complex interplay of genetics, environmental influences and immunometabolic factors. These immunometabolic mechanisms, in particular, those distinguishing between the dry and wet forms of AMD, remain incompletely understood. Utilizing an integrated multiomic approach, incorporating Mendelian Randomization (MR) and single-cell RNA sequencing (scRNA-seq), we have effectively delineated distinct immunometabolic pathways implicated in the development of AMD. Our comprehensive analysis indicates that the androgen-IL10RA-CD16+ monocyte axis could protect against wet AMD. We have also identified several immune and metabolic signatures unique to each AMD subtype, with TNF and Notch signaling pathways being central to disease progression. Furthermore, our analysis, leveraging expression Quantitative Trait Loci (eQTLs) from the Genotype-Tissue Expression (GTEx) project coupled with MR, have highlighted genes such as MTOR, PLA2G7, MAPKAPK3, ANGPTL1, and ARNT as prospective therapeutic targets. The therapeutic potential of these candidate genes was validated with observations from existing drug trial databases. Our robust genetic and transcriptomic approach has identified promising directions for novel AMD interventions, emphasizing the significance of an integrated multiomic approach in tackling this important cause of visual impairment.

immunology↗

bioRxiv2021

High-throughput phenotypic screen for genetic modifiers in patient-derived OPA1 mutant fibroblasts identifies PGS1 as a functional suppressor of mitochondrial fragmentation

Mutations affecting the mitochondrial fusion protein Optic Atrophy 1 (OPA1) cause autosomal dominant optic atrophy (DOA) - one of the most common form of mitochondrial disease. The majority of patients develop isolated optic atrophy, but about 20% of OPA1 mutation carriers manifest more severe neurological deficits as part of a "DOA+" phenotype. OPA1 deficiency causes mitochondrial fragmentation and also disrupts cristae organization, oxidative phosphorylation, mitochondrial DNA (mtDNA) maintenance, and cell viability. It has not yet been established whether phenotypic severity can be modulated by genetic modifiers of OPA1. To better understand the genetic regulation of mitochondrial dynamics, we established a high-throughput imaging pipeline using supervised machine learning (ML) to perform unbiased, quantitative mitochondrial morphology analysis that was coupled with a bespoke siRNA library targeting the entire known mitochondrial proteome (1531 genes), providing a detailed phenotypic screening of human fibroblasts. In control fibroblasts, we identified known and novel genes whose depletion promoted elongation or fragmentation of the mitochondrial network. In DOA+ patient fibroblasts, we identified 91 candidate genes whose depletion prevents mitochondrial fragmentation, including the mitochondrial fission genes DNM1L, MIEF1, and SLC25A46, but also genes not previously linked to mitochondrial dynamics such as Phosphatidyl Glycerophosphate Synthase (PGS1), which belongs to the cardiolipin (CL) synthesis pathway. PGS1 depletion reduces CL content in mitochondria and rebalances mitochondrial dynamics in OPA1-deficient fibroblasts by inhibiting mitochondrial fission, which improves defective respiration, but does not rescue mtDNA depletion, cristae dysmorphology or apoptotic sensitivity. Our data reveal that the multifaceted roles of OPA1 in mitochondria can be functionally uncoupled by modulating mitochondrial lipid metabolism, providing novel insights into the cellular relevance of mitochondrial fragmentation. This study illustrates the power of a first-in-kind objective automated imaging approach to uncover genetic modifiers of mitochondrial disease through high-throughput phenotypic screening of patient fibroblasts.

cell biology↗