Biology subjects

Lopez-Schier, H.

Publications and source records attributed to Lopez-Schier, H..

6 recordsLinked to original sources

bioRxiv2026

Cellular and molecular census of the pleiotropic disease locus Negr1 in zebrafish

A major challenge in precision medicine is to understand the cellular origin of disease-causing genetic alterations. One prominent example is the Negr1 locus, where common non-coding variants are associated with an unusually broad range of human traits and conditions, including body mass index (BMI), major depression, schizophrenia, autism-spectrum conditions and anorexia. Yet, no coding loss-of-function allele has been established as causal. These observations suggest that distinct Negr1-expressing cell populations underlie distinct traits. However, this hypothesis is difficult to test in tractable experimental systems without first determining where this gene may act. To overcome this limitation, we generated a knock-in reporter at the zebrafish Negr1 locus and combined single-cell transcriptomics with whole-brain registration and single-neuron projection mapping. We found that Negr1 is expressed in a graded manner across neuronal classes of the brain and retina, radial glia and astrocyte-like cells, and most consistently in oligodendrocyte progenitor cells. Projection mapping suggests three conserved hubs formed by olfactory bulb projection neurons, tectal periventricular projection neurons and cerebellar eurydendroid cells. Our findings are consistent with the idea that Negr1 pleiotropy arises from dose perturbation of a rather broadly expressed gene. More generally, this integrative approach to produce granular multimodal datasets should enable high-resolution etiological studies in models of human disease.

genomics↗

bioRxiv2026

StressNET: an adaptable deep-learning model for mechanical stress inference in tissues

Mechanical interactions between cells are fundamental to tissue morphogenesis during development and regeneration. Computational methods that infer intercellular stresses from microscopy images of cell shapes offer a non-invasive alternative to experimental perturbation techniques, yet all existing approaches rely on explicit physical models. Here we present StressNET, a Graph Neural Network (GNN) that infers intercellular mechanical stresses directly from tissue geometry, without assuming any underlying physical model. We generated synthetic datasets to train and benchmark StressNET, and demonstrate that its predictions achieve state-of-the-art correlation with experimental stress proxies in zebrafish neuromasts and Xenopus embryos. Analysis of the network's latent space reveals that StressNET learns global organizational principles of mechanical stress distribution, beyond local cell-cell interactions. StressNET is open-source and provides pre-trained models that can be fine-tuned on in vivo data, making it a broadly adaptable tool for studying tissue mechanics across biological systems.

bioinformatics↗

bioRxiv2024

ForSys: non-invasive stress inference from time-lapse microscopy

During tissue development and regeneration, cells interpret and exert mechanical forces that are challenging to measure in vivo. Therefore, stress inference algorithms have emerged as powerful tools to estimate tissue stresses. However, how to incorporate tissue dynamics effectively into the inference remains elusive. Here, we present ForSys, a Python-based software that estimates intercellular stresses and intracellular pressures using time-lapse microscopy. We validated ForSys in silico and in vivo using the well-characterized mucociliary epithelium of the Xenopus embryo. We applied ForSys to study the migrating zebrafish lateral line primordium. We found that stress increases during cell rounding just before cell division and predicted the onset of epithelial rosettogenesis with high accuracy. Finally, we analyzed the development of the zebrafish neuromast and inferred mechanical asymmetries in a cell type-specific adhesion pattern. The versatility and simplicity of ForSys enhance the toolkit for studying spatiotemporal patterns of mechanical forces during tissue morphogenesis in vivo.

systems biology↗

bioRxiv2021

Eya1-dependent homeostasis of morphogenetic territories during collective cell migration

Mutations in the transcriptional co-activator Eya1 cause branchio-oto-renal syndrome (BOR) in humans, and the equivalent conditions in vertebrates. BOR has an incidence of 1/40,000 and is characterized by congenital branchial fistulas, malformations of the inner ear and kidney hypoplasia. Therapeutic interventions for BOR are currently limited to reparative surgery, hearing aids and dialysis. Here we use the mechanosensory lateral line in zebrafish to better understand the role of Eya1 in organogenesis. The lateral line develops from a primordium formed by approximately 150 cells that move together from head to tail of the embryo at a constant velocity. This invariant migration occurs over a trail of Sdf1a chemokine and is controlled by the simultaneous action of two receptors. The CXCR4b is expressed in the front half of the primordium where it acts as a chemokine sensor, whereas the CXCR7b is present in the rear half, serving as a chemokine sink to ensure persistent directionality. We show that the loss of Eya1 strongly reduces the expression of CXCR7b, disrupting the coherent motion of the primordium and leading to lateral-line truncations. We also find evidence of reduced epithelial maturation in primordia lacking Eya1. These findings argue for abnormal collective cell chemotaxis as the origin of organ dysmorphia in BOR.

developmental biology↗

bioRxiv2019

Beyond early development: observing zebrafish over 6 weeks with hybrid optical and optoacoustic imaging

Zebrafish animal models have traditionally been used in developmental biology studies but have recently become promising models of cancer, tissue regeneration and metabolic disorders, as well as efficient platforms for functional genomics and phenotype-based drug discovery. Most studies of zebrafish have examined only the embryonic or larval stages of development, yet many questions in developmental biology and biomedicine require analysis of adults, when zebrafish are large and opaque. Conventional microscopy methods are highly sensitive to light scattering and therefore cannot be applied to zebrafish older than a few weeks. We describe a novel multi-modality system that can observe zebrafish from the larval stage to adulthood. Using a hybrid platform for concurrent selective plane illumination microscopy (SPIM) and optoacoustic mesoscopy we show continuous imaging of fish growth over 47 days of development at a similar object size-to-resolution ratio. Using multiple wavelength illumination over the visible and short-wavelength infrared regions, we reveal that the optoacoustic method can follow GFP-based contrast used in SPIM, enabling molecular imaging interrogation in adult fish. Moreover we optoacoustically reveal many other features of zebrafish based on optical contrast not present in SPIM, including contrast from endogenous blood, water and lipids. The hybrid method presented can extend optical imaging to adult zebrafish employed as model systems for studying long-term processes in development, cancer, diabetes and other disorders.

biophysics↗

bioRxiv2018

Systemic loss of Sarm1 is glioprotective after neurotrauma

The obligate pro-degenerative protein Sarm1 is essential for Wallerian axon degeneration. Inhibition of Sarm1 has been proposed as a promising neuroprotective strategy with clinical relevance. Yet, the conditions that will most benefit from inhibiting Sarm1 remain undefined. Here we use genetics and pharmacology in zebrafish to show that systemic elimination of Sarm1 is glioprotective. Loss of Sarm1 does not affect macrophage recruitment to the wound microenvironment, focal injury resolution, or nerve repair. Unexpectedly, Sarm1 deficiency increases Schwann-cell resistance to toxicity by diverse chemotherapeutic agents after neuronal injury. Yet, synthetic degradation of Sarm1-deficient severed axons reversed this effect, suggesting that glioprotection is non-cell-autonomous. These findings anticipate that interventions aimed at inhibiting Sarm1 can counter heightened glial vulnerability to chemical stressors and may be an effective strategy to reduce chronic consequences of neurotrauma.

cell biology↗