Biology subjects

de Montigny, J.

Publications and source records attributed to de Montigny, J..

5 recordsLinked to original sources

bioRxiv2026

Developmental Synchrony of Retinal Waves, Apoptosis, and Angiogenesis in Postnatal Retina

Postnatal mouse retinal development is a multi-faceted process involving the coordinated interaction of spontaneous neural activity as retinal waves, vascular plexus growth, and programmed cell death. While these processes are known to interact at a coarse scale, the specific mechanisms integrating them have remained elusive. Using large-scale, widefield calcium imaging, high-density multielectrode array recordings, single cell RNA-seq, and immunohistochemistry, we characterise a tightly aligned centrifugal expansion pattern during retinal development. This pattern is common to stage II retinal wave onsets, vascular development, Heme oxygenase-1 (Hmox1) expressing microglia, apoptotic cell markers, and a novel set of auto-fluorescent cluster complexes (ACCs) identified in this study. Apoptotic cells are known to upregulate functional Pannexin1 (PANX-1) hemichannels. These voltage-gated channels release purinergic molecules which act as "eat me" signals to neighbouring microglia. PANX-1 hemichannel blockade with the drug probenecid results in a profound decrease in spontaneous wave frequency and strength, suggesting that retinal waves are indeed triggered by these apoptotic cells. Taken together, our observations suggest that spontaneous waves are initially triggered in hotspots by hyperactive apoptotic RGCs in unvascularised retinal areas. These apoptotic cells release purinergic molecules via PANX-1 hemichannels, leading to wave generation. This hyperactivity leads to local hypoxic conditions, which, coupled with high extracellular ATP concentrations, promotes angiogenesis. Once blood vessels reach a particular hotspot, ATP release activates Hmox1 positive microglia, which engulf the dying RGCs, creating the auto-fluorescent clusters. Herein, we present a unified mechanism linking causally linking early neural activity, programmed cell death and angiogenesis in the mammalian retina.

neuroscience↗

bioRxiv2022

Novel transient cell clusters provide a possible link between early neural activity and angiogenesis in the neonatal mouse retina

Developing neurons become spontaneously active while growing blood vessels begin to irrigate their surroundings. However, surprising little is known about early interactions between neural activity and angiogenesis. In the neonatal mouse retina, spontaneous waves of impulses sweep across the ganglion cell layer (GCL), just underneath the growing superficial vascular plexus. We discovered clusters of transient auto-fluorescent cells in the GCL, forming an annulus that co-localizes with the frontline of the growing plexus. Blood vessel density is highest within cluster areas, suggesting their involvement in angiogenesis. Once the clusters and blood vessels reach the retinal periphery by the end of the first postnatal week, the clusters disappear, eliminated by microglial phagocytosis. Electrical imaging suggests that they have their own electrophysiological signature. Blocking Pannexin1 (PANX1) hemi-channels with probenecid blocks the waves and the fluorescent clusters disappear following prolonged exposure to the drug. Spontaneous waves initiation points follow a developmental center-to-periphery progression similar to the cluster cells. We suggest that these transient cells are specialized, hyperactive neurons residing in the GCL. They generate spontaneous activity hotspots, thereby triggering waves through purinergic paracrine signaling via PANX1 hemi-channels. The strong activity generated around these hotspots triggers angiogenesis, attracting new blood vessels that provide local oxygen supply. Signaling through PANX-1 attracts microglia that establish contact with these cells, eventually leading to their elimination by phagocytosis. These cluster cells may provide the first evidence that specialized transient neuronal populations guide angiogenesis in the developing CNS through neural activity.

neuroscience↗

bioRxiv2021

Retinal self-organization: a model of RGC and SAC mosaic formation

Individual retinal cell types exhibit semi-regular spatial patterns called retinal mosaics. These mosaics enable uniform sampling of visual information and are formed to varying degrees across cell types. Retinal ganglion cells (RGC) and amacrine cells (including starburst amacrine cells (SAC)) are notably known to exhibit such layouts. Mechanisms responsible for the formation of such organised structures and their requirements are still not well understood. Mosaic formation follows three main principles: (1) homotypic cells prevent nearby cells from adopting the same type, (2) cell tangential migration, with homotypic cell repulsion, (3) cell death (with RGCs exhibiting high rates of apoptosis). Here, we use BioDynaMo, an agent-based simulation framework, to build a detailed and mechanistic model of mosaic formation. In particular, we investigate the implications of the three theories for RGCs mosaic formation. We report that the cell migration mechanism yields the most regular mosaics and that cell death can create regular mosaics only if the death rate is kept below 30%, after which cell death has a negative impact on mosaic regularity. In addition, and in accordance with recent studies, we propose here that low density RGC type mosaics exhibit on average low regularities, and thus we question the relevance of regular spacing as a criterion for a group of RGCs to form a RGC type. We also investigate SAC mosaics formation and possible interactions between the ganglion cell layer (GCL) and inner nuclear layer (INL) populations. Investigations are conducted both experimentally and by applying our simulation model to the SAC population. We report that homotypic interactions between the GCL and INL populations during mosaics creation are required to reproduce the observed SAC mosaics characteristics. This suggests that the GCL and INL populations of SACs might not be independent during retinal development. Author SummaryRetinal function depends on cells self-organisation during early development. Understanding the mechanisms underlying this self-organisation could improve not only our comprehension of the retina and its development but also of the cortex. Ultimately, this could lead to novel therapeutic approaches for developmental diseases. Computational models can be of precious help to study this process of self-organisation, given that they are biologically plausible. In this sense, it is important that implemented developmental mechanisms follow the principle of locally available information, without any global knowledge or external supervisor. Here, we follow this principle to investigate mosaic formation during retinal development. In this work, we demonstrate that tangential migration is the only mechanism able to form regular mosaics and that the GCL/INL SAC populations might not be independent during their mosaic formation. More, we question the relevance of regular spacing for RGC types classification.

bioinformatics↗

bioRxiv2020

BioDynaMo: an agent-based simulation platform for scalable computational biology research

MotivationAgent-based modeling is an indispensable tool for studying complex biological systems. However, existing simulators do not always take full advantage of modern hardware and often have a field-specific software design. ResultsWe present a novel simulation platform called BioDynaMo that alleviates both of these problems. BioDynaMo features a general-purpose and high-performance simulation engine. We demonstrate that BioDynaMo can be used to simulate use cases in: neuroscience, oncology, and epidemiology. For each use case we validate our findings with experimental data or an analytical solution. Our performance results show that BioDynaMo performs up to three orders of magnitude faster than the state-of-the-art baseline. This improvement makes it feasible to simulate each use case with one billion agents on a single server, showcasing the potential BioDynaMo has for computational biology research. AvailabilityBioDynaMo is an open-source project under the Apache 2.0 license and is available at www.biodynamo.org. Instructions to reproduce the results are available in supplementary information. Contactlukas.breitwieser@inf.ethz.ch, a.s.hesam@tudelft.nl, omutlu@ethz.ch, r.bauer@surrey.ac.uk Supplementary informationAvailable at https://doi.org/10.5281/zenodo.4501515.

systems biology↗

bioRxiv2019

Evidence for novel transient clusters of cholinergic ganglion cells in the neonatal mouse retina

Waves of spontaneous activity sweep across the neonatal mouse retinal ganglion cell (RGC) layer, driven by directly interconnected cholinergic starburst amacrine cells from postnatal day (P) 0-10, followed by waves driven by glutamatergic bipolar cells. We found transient clusters of auto-fluorescent cells in the RGC layer during the period of cholinergic waves. They appear around the optic nerve head at P2 and become gradually displaced towards the periphery between P2-8 and then they disappear. Pan-retinal multielectrode array recordings reveal that cholinergic wave origins follow a similar, non-random developmental center-to-periphery pattern. Electrical imaging unmasks hotspots of dipole electrical activity occurring in the vicinity of wave origins. We propose that these activity hotspots are the sites for wave initiation and may originate from the transient cell clusters, reminiscent of activity in transient subplate neurons in the developing cortex, suggesting a universal hyper-excitability mechanism in developing CNS networks during the critical period for brain wiring.

neuroscience↗