Papers by Juanjo Sanz Ezquerro
4D reconstruction of developmental trajectories using spherical harmonics
SummaryAlthough the full embryonic development of species such as Drosophila and zebrafish can be... more SummaryAlthough the full embryonic development of species such as Drosophila and zebrafish can be 3D imaged in real time, this is not true for mammalian organs, as normal organogenesis cannot be recapitulated in vitro. Currently available 3D data is therefore ex vivo images which provide only a snap shot of development at discrete moments in time. Here we propose a computer-based approach to recreate the continuous evolution in time and space of developmental stages from 3D volumetric images. Our method uses the mathematical approach of spherical harmonics to re-map discrete shape data into a space in which facilitates a smooth interpolation over time. We tested our approach on mouse limb buds (from E10 to E12.5) and embryonic hearts (from 10 to 29 somites). A key advantage of the method is that the resulting 4D trajectory takes advantage of all the available data (i.e. it is not dominated by the choice of a few “ideal” images), while also being able to interpolate well through time...
Development, 2000
The polarising region expresses the signalling molecule sonic hedgehog (Shh), and is an embryonic... more The polarising region expresses the signalling molecule sonic hedgehog (Shh), and is an embryonic signalling centre essential for outgrowth and patterning of the vertebrate limb. Previous work has suggested that there is a buffering mechanism that regulates polarising activity. Little is known about how the number of Shh-expressing cells is controlled but, paradoxically, the polarising region appears to overlap with the posterior necrotic zone, a region of programmed cell death. We have investigated how Shh expression and cell death respond when levels of polarising activity are altered, and show an autoregulatory effect of Shh on Shh expression and that Shh affects cell death in the posterior necrotic zone. When we increased Shh signalling, by grafting polarising region cells or applying Shh protein beads, this led to a reduction in the endogenous Shh domain and an increase in posterior cell death. In contrast, cells in other necrotic regions of the limb bud, including the interdig...
Candida albicans is a frequent aetiologic agent of sepsis associated with high mortality in immun... more Candida albicans is a frequent aetiologic agent of sepsis associated with high mortality in immunocompromised patients. Developing new antifungal therapies is a medical need due to the low efficiency and resistance to current antifungal drugs. Here, we show that p38c and p38d regulate the innate immune response to C. albicans. We describe a new TAK1-TPL2-MKK1-ERK1/2 pathway in macrophages, which is activated by Dectin-1 engagement and positively regulated by p38c/p38d. In mice, p38c/p38d deficiency protects against C. albicans infection by increasing ROS and iNOS production and thus the antifungal capacity of neutrophils and macrophages, and by decreasing the hyper-inflammation that leads to severe host damage. Leucocyte recruitment to infected kidneys and production of inflammatory mediators are decreased in p38c/d-null mice, reducing septic shock. p38c/p38d in myeloid cells are critical for this effect. Moreover, pharmacological inhibition of p38c/p38d in mice reduces fungal burde...
Development, 2001
We have investigated the role of FGFs in the control of programmed cell death during limb develop... more We have investigated the role of FGFs in the control of programmed cell death during limb development by analyzing the effects of increasing and blocking FGF signaling in the avian limb bud. BMPs are currently considered as the signals responsible for cell death. Here we show that FGF signaling is also necessary for apoptosis and that the establishment of the areas of cell death is regulated by the convergence of FGF- and BMP-mediated signaling pathways. As previously demonstrated, cell death is inhibited for short intervals (12 hours) after administration of FGFs. However, this initial inhibition is followed (24 hours) by a dramatic increase in cell death, which can be abolished by treatments with a BMP antagonist (Noggin or Gremlin). Conversely, blockage of FGF signaling by applying a specific FGF-inhibitor (SU5402) into the interdigital regions inhibits both physiological cell death and that mediated by exogenous BMPs. Furthermore, FGF receptors 1, 2 and 3 are expressed in the au...
Frontiers is more than just an open-access publisher of scholarly articles: it is a pioneering ap... more Frontiers is more than just an open-access publisher of scholarly articles: it is a pioneering approach to the world of academia, radically improving the way scholarly research is managed. The grand vision of Frontiers is a world where all people have an equal opportunity to seek, share and generate knowledge. Frontiers provides immediate and permanent online open access to all its publications, but this alone is not enough to realize our grand goals. Frontiers Journal Series The Frontiers Journal Series is a multi-tier and interdisciplinary set of open-access, online journals, promising a paradigm shift from the current review, selection and dissemination processes in academic publishing. All Frontiers journals are driven by researchers for researchers; therefore, they constitute a service to the scholarly community. At the same time, the Frontiers Journal Series operates on a revolutionary invention, the tiered publishing system, initially addressing specific communities of scholars, and gradually climbing up to broader public understanding, thus serving the interests of the lay society, too. Dedication to Quality Each Frontiers article is a landmark of the highest quality, thanks to genuinely collaborative interactions between authors and review editors, who include some of the world's best academicians. Research must be certified by peers before entering a stream of knowledge that may eventually reach the public-and shape society; therefore, Frontiers only applies the most rigorous and unbiased reviews. Frontiers revolutionizes research publishing by freely delivering the most outstanding research, evaluated with no bias from both the academic and social point of view. By applying the most advanced information technologies, Frontiers is catapulting scholarly publishing into a new generation. What are Frontiers Research Topics? Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial
Journal of general …, 1996
The RNA polymerase activity and PB1 binding of influenza virus PA mutants were studied using an i... more The RNA polymerase activity and PB1 binding of influenza virus PA mutants were studied using an in vivo-reconstituted polymerase assay and a two hybrid system. Deletions covering the whole PA protein abolished polymerase activity, but the deletion of the 154 N-terminal amino acids allowed PB1 binding, indicating that the PA protein N terminus is not absolutely required for this interaction. Further internal or C-terminal deletions abolished PB1 interaction, suggesting that most of the protein is involved in this association. As a novel finding we showed that a single amino acid insertion mutant, PAI672, was responsible for a temperature-sensitive phenotype. Hutant PAS509, which had a serine insertion at position 509, bound to PBI like wild-type PA but did not show any polymerase activity. Over-expression of PAS509 interfered with the polymerase activity of wild-type PA, identifying PAS509 as a dominant negative mutant.
Journal of anatomy, 2003
Signalling interactions between the polarizing region, which produces SHH, and the apical ectoder... more Signalling interactions between the polarizing region, which produces SHH, and the apical ectodermal ridge, which produces FGFs, are essential for outgrowth and patterning of vertebrate limbs. However, mechanisms that mediate translation of early positional information of cells into ...
Nature Methods, 2008
Quantitative mapping of the normal tissue dynamics of an entire developing mammalian organ has no... more Quantitative mapping of the normal tissue dynamics of an entire developing mammalian organ has not been achieved so far but is essential to understand developmental processes and to provide quantitative data for computational modeling. We developed a four-dimensional (4D) imaging technique that can be used to quantitatively image tissue movements and dynamic GFP expression domains in a growing transgenic mouse limb by time-lapse optical projection tomography (OPT).
Journal of …, 1996
We have previously described the fact that the individual expression of influenza virus PA protei... more We have previously described the fact that the individual expression of influenza virus PA protein induced a generalized proteolysis (
Regulation of Tbx3 expression by anteroposterior signalling in vertebrate limb development
Developmental Biology, 2002
Tbx3, a T-box gene family member related to the Drosophila gene optomotor blind (omb) and encodin... more Tbx3, a T-box gene family member related to the Drosophila gene optomotor blind (omb) and encoding a transcription factor, is expressed in anterior and posterior stripes in developing chick limb buds. Tbx3 haploinsufficiency has been linked with the human condition ulnar–mammary syndrome, in which predominantly posterior defects occur in the upper limb. Omb is expressed in Drosophila wing development in
Journal of …, 2000
The PA subunit of the influenza virus polymerase complex is a phosphorylated protein that induces... more The PA subunit of the influenza virus polymerase complex is a phosphorylated protein that induces a proteolytic process that decreases its own accumulation levels and those of coexpressed proteins. The amino-terminal third of the protein is responsible for the induction of ...
…, 2011
The apical ectodermal ridge (AER) is a specialized epithelium located at the distal edge of the l... more The apical ectodermal ridge (AER) is a specialized epithelium located at the distal edge of the limb bud that directs outgrowth along the proximodistal axis. Although the molecular basis for its function is well known, the cellular mechanisms that lead to its maturation are not fully ...
Developmental …, 2007
Sonic Hedgehog (Shh) signaling by the polarizing region, at the posterior of the vertebrate limb ... more Sonic Hedgehog (Shh) signaling by the polarizing region, at the posterior of the vertebrate limb bud, is pivotal in determining digit number and identity. Shh establishes a gradient of the bifunctional transcriptional effector, Gli3, with high levels of full-length activator (Gli3A) in the posterior ...
Differentiation, 2001
A detailed and precise picture is being pieced together about how the pattern of digits develops ... more A detailed and precise picture is being pieced together about how the pattern of digits develops in vertebrate limbs. What is particularly exciting is that it will soon be possible to trace the process all the way from establishment of a signalling centre in a small bud of ...
5 Pyst1/MKP3, a novel dual-specificity phosphatase, and FGF signalling in chick limb development
Journal of anatomy, 2002
International Journal of Molecular Sciences
p38 Mitogen activated protein kinases (p38MAPK) are a highly evolutionary conserved group of prot... more p38 Mitogen activated protein kinases (p38MAPK) are a highly evolutionary conserved group of protein kinases, which are central for cell adaptation to environmental changes as well as for immune response, inflammation, tissue regeneration, and tumour formation [...]
EMBO molecular medicine, May 16, 2018
is a frequent aetiologic agent of sepsis associated with high mortality in immunocompromised pati... more is a frequent aetiologic agent of sepsis associated with high mortality in immunocompromised patients. Developing new antifungal therapies is a medical need due to the low efficiency and resistance to current antifungal drugs. Here, we show that p38γ and p38δ regulate the innate immune response to We describe a new TAK1-TPL2-MKK1-ERK1/2 pathway in macrophages, which is activated by Dectin-1 engagement and positively regulated by p38γ/p38δ. In mice, p38γ/p38δ deficiency protects against infection by increasing ROS and iNOS production and thus the antifungal capacity of neutrophils and macrophages, and by decreasing the hyper-inflammation that leads to severe host damage. Leucocyte recruitment to infected kidneys and production of inflammatory mediators are decreased in p38γ/δ-null mice, reducing septic shock. p38γ/p38δ in myeloid cells are critical for this effect. Moreover, pharmacological inhibition of p38γ/p38δ in mice reduces fungal burden, revealing that these p38MAPKs may be th...
Frontiers in Cell and Developmental Biology
Development (Cambridge, England), 2000
It has been proposed that digit identity in chick limb bud is specified in a dose-dependent fashi... more It has been proposed that digit identity in chick limb bud is specified in a dose-dependent fashion by a long-range morphogen, produced by the polarising region. One candidate is Sonic hedgehog (Shh) protein, but it is not clear whether Shh acts long or short range or via Bmps. Here we dissect the relationship between Shh and Bmp signalling. We show that Shh is necessary not only for initiating bmp2 expression but also for sustaining its expression during the period when additional digits are being specified. We also show that we can reproduce much of the effect of Shh during this period by applying only Bmp2. We further demonstrate that it is Bmps that are responsible for digit specification by transiently adding Noggin or Bmp antibodies to limbs treated with Shh. In such limbs, multiple additional digits still form but they all have the same identity. We also explored time dependency and range of Shh signalling by examining ptc expression. We show that high-level ptc expression is...
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Papers by Juanjo Sanz Ezquerro