Research Timeline
Published Work
Small Methods 2025, 9(9) Art. No. e01956
Purine Molecular Interactions Determine Anisotropic Shape of Zebrafish Biogenic Crystals.
Rothkegel J, Kaufmann S, Wilsch-Bräuninger M, Lopes C, Mateus R
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Across phyla, many organisms self-organize crystals, for functions like vision, pigmentation, and metabolite storage. In zebrafish, a vertebrate known for its crystal-based color patterns, iridophores concentrate purines in membrane-bound organelles, the iridosomes. Inside these vesicles, crystals assemble into large, flat, and thin hexagons following unknown mechanisms that defy typical thermodynamic interactions. Here, we investigate the development of zebrafish iridosomal crystals by using live imaging, cryoFIB-SEM, and novel morphometric analysis pipelines. In doing so, we find that crystal growth predominantly occurs along the b-crystallographic axis, producing their characteristic anisotropic shape. By performing comparative genetic analyses in vivo and reproducing such conditions in silico, we uncover that the zebrafish crystals' in-plane hydrogen bond molecular structure is the main determinant for the observed crystal anisotropy. Macroscopically, the b-axis anisotropy is controlled by the ratio of guanine-to-hypoxanthine in the iridosome, without affecting the other axes. At the atomic level, the extent of the (100) facet anisotropy depends entirely on the type, number, and strength of molecular H-bonds within the crystal lattice. Mechanistically, our work shows that purine diversity and availability inside the zebrafish iridosome is key to form an anisotropic crystal lattice, leading to the observed functional crystal shapes.
Cell Reports 2020 30, 4292–4302
BMP signalling gradient scaling in the zebrafish pectoral fin
Mateus R, Holtzer L, Seum C, Hadjivasiliou Z, Dubois M, Julicher F, Gonzalez-Gaitan M.
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Secreted growth factors can act as morphogens that form spatial concentration gradients in developing organs, thereby controlling growth and patterning. For some morphogens, adaptation of the gradients to tissue size allows morphological patterns to remain proportioned as the organs grow. In the zebrafish pectoral fin, we found that BMP signalling forms a two‑dimensional gradient. The length of the gradient scales with tissue length and its amplitude increases with fin size according to a power-law. Gradient scaling and amplitude power‑laws are signatures of growth control by time derivatives of morphogenetic signalling: cell division correlates with the fold change over time of the cellular signalling levels. We show that Smoc1 regulates BMP gradient scaling and growth in the fin. Smoc1 scales the gradient by means of a feedback loop: Smoc1 is a BMP agonist and BMP signalling represses Smoc1 expression. Our work uncovers a novel layer of morphogen regulation during vertebrate appendage development.
Cell Reports 2020 30, 4292–4302
BMP signalling gradient scaling in the zebrafish pectoral fin
Mateus R, Holtzer L, Seum C, Hadjivasiliou Z, Dubois M, Julicher F, Gonzalez-Gaitan M.
​
Secreted growth factors can act as morphogens that form spatial concentration gradients in developing organs, thereby controlling growth and patterning. For some morphogens, adaptation of the gradients to tissue size allows morphological patterns to remain proportioned as the organs grow. In the zebrafish pectoral fin, we found that BMP signalling forms a two‑dimensional gradient. The length of the gradient scales with tissue length and its amplitude increases with fin size according to a power-law. Gradient scaling and amplitude power‑laws are signatures of growth control by time derivatives of morphogenetic signalling: cell division correlates with the fold change over time of the cellular signalling levels. We show that Smoc1 regulates BMP gradient scaling and growth in the fin. Smoc1 scales the gradient by means of a feedback loop: Smoc1 is a BMP agonist and BMP signalling represses Smoc1 expression. Our work uncovers a novel layer of morphogen regulation during vertebrate appendage development.
Semin Cell Dev Biol 2025, 174 Art. No. 103641
Start-Shape-Stop: Cell communication mechanisms controlling organ size.
Ribas L, Mateus R
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Accurate growth control is critical for the achievement of proportional organs during animal development and repair processes. Either extra or deficient growth rates lead to organ functional impairment. The understanding of how organs acquire, recover, and fine-tune their final size has been a long-lasting biological problem. How do organs measure their current size? This review is centered on this question through the lens of the physical properties governing cell communication mechanisms. In particular, we highlight and discuss new insight into the dynamic connections between several cellular control mechanisms that operate at different timescales to regulate organ growth and morphogenesis.
Nat Chem Biol 2025, 21(3) 383-392
Genetic control over biogenic crystal morphogenesis in zebrafish.
Deis R, Lerer-Goldshtein T, Baiko O, Eyal Z, Brenman-Begin D, Goldsmith M, Kaufmann S, Heinig U, Dong Y, Lushchekina S, Varsano N, Olender T, Kupervaser M, Porat Z, Levin-Zaidman S, Pinkas I, Mateus R, Gur D
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Organisms evolve mechanisms that regulate the properties of biogenic crystals to support a wide range of functions, from vision and camouflage to communication and thermal regulation. Yet, the mechanism underlying the formation of diverse intracellular crystals remains enigmatic. Here we unravel the biochemical control over crystal morphogenesis in zebrafish iridophores. We show that the chemical composition of the crystals determines their shape, particularly through the ratio between the nucleobases guanine and hypoxanthine. We reveal that these variations in composition are genetically controlled through tissue-specific expression of specialized paralogs, which exhibit remarkable substrate selectivity. This orchestrated combination grants the organism with the capacity to generate a broad spectrum of crystal morphologies. Overall, our findings suggest a mechanism for the morphological and functional diversity of biogenic crystals and may, thus, inspire the development of genetically designed biomaterials and medical therapeutics.
Evol Dev 2024, 26(3) Art. No. e12475
Developmental plasticity and variability in the formation of egg-spots, a pigmentation ornament in the cichlid Astatotilapia calliptera.
Clark B, Hickey A, Marconi A, Fischer B, Elkin J, Mateus R, Santos ME
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Vertebrate pigmentation patterns are highly diverse, yet we have a limited understanding of how evolutionary changes to genetic, cellular, and developmental mechanisms generate variation. To address this, we examine the formation of a sexually-selected male ornament exhibiting inter- and intraspecific variation, the egg-spot pattern, consisting of circular yellow-orange markings on the male anal fins of haplochromine cichlid fishes. We focus on Astatotilapia calliptera, the ancestor-type species of the Malawi cichlid adaptive radiation of over 850 species. We identify a key role for iridophores in initializing egg-spot aggregations composed of iridophore-xanthophore associations. Despite adult sexual dimorphism, aggregations initially form in both males and females, with development only diverging between the sexes at later stages. Unexpectedly, we found that the timing of egg-spot initialization is plastic. The earlier individuals are socially isolated, the earlier the aggregations form, with iridophores being the cell type that responds to changes to the social environment. Furthermore, we observe apparent competitive interactions between adjacent egg-spot aggregations, which strongly suggests that egg-spot patterning results mostly from cell-autonomous cellular interactions. Together, these results demonstrate that A. calliptera egg-spot development is an exciting model for investigating pigment pattern formation at the cellular level in a system with developmental plasticity, sexual dimorphism, and intraspecific variation. As A. calliptera represents the ancestral bauplan for egg-spots, these findings provide a baseline for informed comparisons across the incredibly diverse Malawi cichlid radiation.​
Current Opinion in Cell Biology 2021,73:50–57
Growth across scales: Dynamic signaling impacts tissue size and shape
Mateus R, Fuhrmann J, Dye NA.
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Organ and tissue growth result from an integration of biophysical communication across biological scales, both in time and space. In this review, we highlight new insight into the dynamic connections between control mechanisms operating at different length scales. First, we consider how the dynamics of chemical and electrical signaling in the shape of gradients or waves affect spatiotemporal signal interpretation. Then, we discuss the mechanics underlying dynamic cell behavior during oriented tissue growth, followed by the connections between signaling at the tissue and organismal levels.
Cell Reports 2020 30, 4292–4302
BMP signalling gradient scaling in the zebrafish pectoral fin
Mateus R, Holtzer L, Seum C, Hadjivasiliou Z, Dubois M, Julicher F, Gonzalez-Gaitan M.
​
Secreted growth factors can act as morphogens that form spatial concentration gradients in developing organs, thereby controlling growth and patterning. For some morphogens, adaptation of the gradients to tissue size allows morphological patterns to remain proportioned as the organs grow. In the zebrafish pectoral fin, we found that BMP signalling forms a two‑dimensional gradient. The length of the gradient scales with tissue length and its amplitude increases with fin size according to a power-law. Gradient scaling and amplitude power‑laws are signatures of growth control by time derivatives of morphogenetic signalling: cell division correlates with the fold change over time of the cellular signalling levels. We show that Smoc1 regulates BMP gradient scaling and growth in the fin. Smoc1 scales the gradient by means of a feedback loop: Smoc1 is a BMP agonist and BMP signalling represses Smoc1 expression. Our work uncovers a novel layer of morphogen regulation during vertebrate appendage development.
Cell Reports 2020 30, 4292–4302
BMP signalling gradient scaling in the zebrafish pectoral fin
Mateus R, Holtzer L, Seum C, Hadjivasiliou Z, Dubois M, Julicher F, Gonzalez-Gaitan M.
​
Secreted growth factors can act as morphogens that form spatial concentration gradients in developing organs, thereby controlling growth and patterning. For some morphogens, adaptation of the gradients to tissue size allows morphological patterns to remain proportioned as the organs grow. In the zebrafish pectoral fin, we found that BMP signalling forms a two‑dimensional gradient. The length of the gradient scales with tissue length and its amplitude increases with fin size according to a power-law. Gradient scaling and amplitude power‑laws are signatures of growth control by time derivatives of morphogenetic signalling: cell division correlates with the fold change over time of the cellular signalling levels. We show that Smoc1 regulates BMP gradient scaling and growth in the fin. Smoc1 scales the gradient by means of a feedback loop: Smoc1 is a BMP agonist and BMP signalling represses Smoc1 expression. Our work uncovers a novel layer of morphogen regulation during vertebrate appendage development.
Cell Reports 2020 30, 4292–4302
BMP signalling gradient scaling in the zebrafish pectoral fin
Mateus R, Holtzer L, Seum C, Hadjivasiliou Z, Dubois M, Julicher F, Gonzalez-Gaitan M.
​
Secreted growth factors can act as morphogens that form spatial concentration gradients in developing organs, thereby controlling growth and patterning. For some morphogens, adaptation of the gradients to tissue size allows morphological patterns to remain proportioned as the organs grow. In the zebrafish pectoral fin, we found that BMP signalling forms a two‑dimensional gradient. The length of the gradient scales with tissue length and its amplitude increases with fin size according to a power-law. Gradient scaling and amplitude power‑laws are signatures of growth control by time derivatives of morphogenetic signalling: cell division correlates with the fold change over time of the cellular signalling levels. We show that Smoc1 regulates BMP gradient scaling and growth in the fin. Smoc1 scales the gradient by means of a feedback loop: Smoc1 is a BMP agonist and BMP signalling represses Smoc1 expression. Our work uncovers a novel layer of morphogen regulation during vertebrate appendage development.
Journal of Cell Science 2019 132: jcs231993
Yap induces osteoblast differentiation by modulating Bmp signalling during zebrafish caudal fin regeneration.
Brandão AS, Bensimon-Brito A, Lourenço R, Borbinha J, Soares AR, Mateus R, Jacinto A.
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Osteoblast differentiation is a key process for bone homeostasis and repair. Multiple signalling pathways have been associated with osteoblast differentiation, yet much remains unknown on how this process is regulated in vivo Previous studies have proposed that the Hippo pathway transcriptional co-activators YAP and TAZ (also known as YAP1 and WWTR1, respectively) maintain progenitor stemness and inhibit terminal differentiation of osteoblasts, whereas others suggest they potentiate osteoblast differentiation and bone formation. Here, we use zebrafish caudal fin regeneration as a model to clarify how the Hippo pathway regulates de novo bone formation and osteoblast differentiation. We demonstrate that Yap inhibition leads to accumulation of osteoprogenitors and prevents osteoblast differentiation in a cell non-autonomous manner. This effect correlates with a severe impairment of Bmp signalling in osteoblasts, likely by suppressing the expression of the ligand bmp2a in the surrounding mesenchymal cells. Overall, our findings provide a new mechanism of bone formation through the Hippo-Yap pathway, integrating Yap in the signalling cascade that governs osteoprogenitor maintenance and subsequent differentiation during zebrafish caudal fin regeneration.
Biochim Biophys Acta Mol Cell Biol Lipids. 2017 Feb;1862(2):210-220
Cholesteryl hemiesters alter lysosome structure and function and induce proinflammatory cytokine production in macrophages.
Domingues N, Estronca LMBB, Silva J, Encarnação MR, Mateus R, Silva D, Santarino IB, Saraiva M, Soares MIL, Pinho E Melo TMVD, Jacinto A, Vaz WLC, Vieira OV.
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Cholesteryl hemiesters are oxidation products of polyunsaturated fatty acid esters of cholesterol. Their oxo-ester precursors have been identified as important components of the "core aldehydes" of human atheromata and in oxidized lipoproteins (Ox-LDL). We had previously shown, for the first time, that a single compound of this family, cholesteryl hemisuccinate (ChS), is sufficient to cause irreversible lysosomal lipid accumulation (lipidosis), and is toxic to macrophages. These features, coupled to others such as inflammation, are typically seen in atherosclerosis. To obtain insights into the mechanism of cholesteryl hemiester-induced pathological changes in lysosome function and induction of inflammation in vitro and assess their impact in vivo.
We have examined the effects of ChS on macrophages (murine cell lines and primary cultures) in detail. Specifically, lysosomal morphology, pH, and proteolytic capacity were examined. Exposure of macrophages to sub-toxic ChS concentrations caused enlargement of the lysosomes, changes in their luminal pH, and accumulation of cargo in them. In primary mouse bone marrow-derived macrophages (BMDM), ChS-exposure increased the secretion of IL-1β, TNF-α and IL-6. In zebrafish larvae (wild-type AB and PU.1:EGFP), fed with a ChS-enriched diet, we observed lipid accumulation, myeloid cell-infiltration in their vasculature and decrease in larval survival. Under the same conditions the effects of ChS were more profound than the effects of free cholesterol (FC). Our data strongly suggest that cholesteryl hemiesters are pro-atherogenic lipids able to mimic features of Ox-LDL both in vitro and in vivo.
Development. 2015 Aug 15;142(16):2752-63
Control of tissue growth by Yap relies on cell density and F-actin in zebrafish fin regeneration.
Mateus R, Lourenço R, Fang Y, Brito G, Farinho A, Valério F, Jacinto A.
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Caudal fin regeneration is characterized by a proliferation boost in the mesenchymal blastema that is controlled precisely in time and space. This allows a gradual and robust restoration of original fin size. However, how this is established and regulated is not well understood. Here, we report that Yap, the Hippo pathway effector, is a chief player in this process: functionally manipulating Yap during regeneration dramatically affects cell proliferation and expression of key signaling pathways, impacting regenerative growth. The intracellular location of Yap is tightly associated with different cell densities along the blastema proximal-distal axis, which correlate with alterations in cell morphology, cytoskeleton and cell-cell contacts in a gradient-like manner. Importantly, Yap inactivation occurs in high cell density areas, conditional to F-actin distribution and polymerization. We propose that Yap is essential for fin regeneration and that its function is dependent on mechanical tension, conferred by a balancing act of cell density and cytoskeleton activity.
J Neurosci. 2013 Feb 27;33(9):3834-43
Identification of nonvisual photomotor response cells in the vertebrate hindbrain.
Kokel D, Dunn TW, Ahrens MB, Alshut R, Cheung CY, Saint-Amant L, Bruni G, Mateus R, van Ham TJ, Shiraki T, Fukada Y, Kojima D, Yeh JR, Mikut R, von Lintig J, Engert F, Peterson RT.
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Nonvisual photosensation enables animals to sense light without sight. However, the cellular and molecular mechanisms of nonvisual photobehaviors are poorly understood, especially in vertebrate animals. Here, we describe the photomotor response (PMR), a robust and reproducible series of motor behaviors in zebrafish that is elicited by visual wavelengths of light but does not require the eyes, pineal gland, or other canonical deep-brain photoreceptive organs. Unlike the relatively slow effects of canonical nonvisual pathways, motor circuits are strongly and quickly (seconds) recruited during the PMR behavior. We find that the hindbrain is both necessary and sufficient to drive these behaviors. Using in vivo calcium imaging, we identify a discrete set of neurons within the hindbrain whose responses to light mirror the PMR behavior. Pharmacological inhibition of the visual cycle blocks PMR behaviors, suggesting that opsin-based photoreceptors control this behavior. These data represent the first known light-sensing circuit in the vertebrate hindbrain.
PLoS One. 2012;7(12):e51766
In vivo cell and tissue dynamics underlying zebrafish fin fold regeneration.
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Mateus R, Pereira T, Sousa S, de Lima JE, Pascoal S, Saúde L, Jacinto A.
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Zebrafish (Danio rerio) has a remarkable capacity to regenerate many organs and tissues. During larval stages the fin fold allows the possibility of performing long time-lapse imaging making this system very appealing to study the relationships between tissue movements, cell migration and proliferation necessary for the regeneration process.Through the combined use of transgenic fluorescently-labeled animals and confocal microscopy imaging, we characterized in vivo the complete fin fold regeneration process. We show, for the first time, that there is an increase in the global rate of epidermal growth as a response to tissue loss. Also enhanced significantly is cell proliferation, which upon amputation happens in a broad area concerning the amputation level and not in a blastema-restricted way. This reveals a striking difference with regard to the adult fin regeneration system. Finally, an accumulation of migratory, shape-changing fibroblasts occurs proximally to the wound area, resembling a blastemal-like structure, which may act as a signaling center for the regeneration process to proceed. These findings provide a novel in vivo description of fundamental mechanisms occurring during the fin fold regeneration process, thereby contributing to a better knowledge of this regenerative system and to reveal variations in the epimorphic regeneration field.
Nat Chem Biol. 2010 Mar;6(3):231-237
Rapid behavior-based identification of neuroactive small molecules in the zebrafish.
Kokel D, Bryan J, Laggner C, White R, Cheung CY, Mateus R, Healey D, Kim S, Werdich AA, Haggarty SJ, Macrae CA, Shoichet B, Peterson RT.
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Neuroactive small molecules are indispensable tools for treating mental illnesses and dissecting nervous system function. However, it has been difficult to discover novel neuroactive drugs. Here, we describe a high-throughput, behavior-based approach to neuroactive small molecule discovery in the zebrafish. We used automated screening assays to evaluate thousands of chemical compounds and found that diverse classes of neuroactive molecules caused distinct patterns of behavior. These 'behavioral barcodes' can be used to rapidly identify new psychotropic chemicals and to predict their molecular targets. For example, we identified new acetylcholinesterase and monoamine oxidase inhibitors using phenotypic comparisons and computational techniques. By combining high-throughput screening technologies with behavioral phenotyping in vivo, behavior-based chemical screens can accelerate the pace of neuroactive drug discovery and provide small-molecule tools for understanding vertebrate behavior.