Hubrecht Institute for Developmental Biology and Stem Cell Research

Utrecht, Netherlands

Hubrecht Institute for Developmental Biology and Stem Cell Research

Utrecht, Netherlands
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Mallo M.,Instituto Gulbenkian Of Ciencia | Mallo M.,University of Lisbon | Wellik D.M.,University of Michigan | Deschamps J.,Hubrecht Institute for Developmental Biology and Stem Cell Research
Developmental Biology | Year: 2010

Several decades have passed since the discovery of Hox genes in the fruit fly Drosophila melanogaster. Their unique ability to regulate morphologies along the anteroposterior (AP) axis (Lewis, 1978) earned them well-deserved attention as important regulators of embryonic development. Phenotypes due to loss- and gain-of-function mutations in mouse Hox genes have revealed that the spatio-temporally controlled expression of these genes is critical for the correct morphogenesis of embryonic axial structures. Here, we review recent novel insight into the modalities of Hox protein function in imparting specific identity to anatomical regions of the vertebral column, and in controlling the emergence of these tissues concomitantly with providing them with axial identity. The control of these functions must have been intimately linked to the shaping of the body plan during evolution. © 2010 Elsevier Inc.


Giuliani F.,Hubrecht Institute for Developmental Biology and Stem Cell Research | Grieve A.,Hubrecht Institute for Developmental Biology and Stem Cell Research | Rabouille C.,Hubrecht Institute for Developmental Biology and Stem Cell Research
Current Opinion in Cell Biology | Year: 2011

Most proteins follow the classical secretory pathway from the endoplasmic reticulum, via the Golgi, to the plasma membrane or extracellular medium. However, some proteins reach these final destinations by two alternative routes. One sustains the extracellular delivery of cytoplasmic proteins that lack a signal peptide, the other supports the transport of transmembrane proteins to the plasma membrane in a manner that bypasses the Golgi. Here, we highlight the observation that some unconventional secretion events are triggered by cellular stress. Furthermore, one Golgi protein, Golgi Re-Assembly and Stacking Protein (GRASP), has been shown to be essential to both types of unconventional secretion and we discuss ways in which it may support these events in a Golgi-independent manner. © 2011 Elsevier Ltd.


Deschamps J.,Hubrecht Institute for Developmental Biology and Stem Cell Research
Nature Genetics | Year: 2016

The recently discovered chromatin compartments called topologically associating domains (TADs) are essential for the three-dimensional organization of regulatory interactions driving gene expression. A new study documents the emergence of a TAD flanking the amphioxus Hox cluster, prefiguring the vertebrate anterior Hox TAD and preceding the appearance of the concurring posterior Hox TAD. © 2016 Nature America, Inc.


Twiss F.,Hubrecht Institute for Developmental Biology and Stem Cell Research | De Rooij J.,Hubrecht Institute for Developmental Biology and Stem Cell Research
Cellular and Molecular Life Sciences | Year: 2013

Mechanical forces are increasingly recognized as central factors in the regulation of tissue morphogenesis and homeostasis. Central to the transduction of mechanical information into biochemical signaling is the contractile actomyosin cytoskeleton. Fluctuations in actomyosin contraction are sensed by tension sensitive systems at the interface between actomyosin and cell adhesion complexes. We review the current knowledge about the mechanical coupling of cell-cell junctions to the cytoskeleton and highlight the central role of α-catenin in this linkage. We assemble current knowledge about α-catenin's regulation by tension and about its interactions with a diversity of proteins. We present a model in which α-catenin is a force-regulated platform for a machinery of proteins that orchestrates local cortical remodeling in response to force. Finally, we highlight recently described fundamental processes in tissue morphogenesis and argue where and how this α-catenin-dependent cadherin mechanotransduction may be involved. © 2013 Springer Basel.


Farin H.F.,Hubrecht Institute for Developmental Biology and Stem Cell Research | Van Es J.H.,Hubrecht Institute for Developmental Biology and Stem Cell Research | Clevers H.,Hubrecht Institute for Developmental Biology and Stem Cell Research
Gastroenterology | Year: 2012

Background & Aims: Wnt signaling regulates multiple aspects of intestinal physiology, including stem cell maintenance. Paneth cells support stem cells by secreting Wnt, but little is known about the exact sources and primary functions of individual Wnt family members. Methods: We analyzed intestinal tissues and cultured epithelial cells from adult mice with conditional deletion of Wnt3 (Vil-CreERT2;Wnt3fl/fl mice). We also analyzed intestinal tissues and cells from Atoh1 mutant mice, which lack secretory cells. Results: Unexpectedly, Wnt3 was dispensable for maintenance of intestinal stem cells in mice, indicating a redundancy of Wnt signals. By contrast, cultured crypt organoids required Paneth cell-derived Wnt3. Addition of exogenous Wnt, or coculture with mesenchymal cells, restored growth of Vil-CreERT2;Wnt3fl/fl crypt organoids. Intestinal organoids from Atoh1 mutant mice did not grow or form Paneth cells; addition of Wnt3 allowed growth in the absence of Paneth cells. Wnt signaling had a synergistic effect with the Lgr4/5 ligand R-spondin to induce formation of Paneth cells. Mosaic expression of Wnt3 in organoids using a retroviral vector promoted differentiation of Paneth cells in a cell-autonomous manner. Conclusions: Wnt is part of a signaling loop that affects homeostasis of intestinal stem and Paneth cells in mice. Wnt3 signaling is required for growth and development of organoid cultures, whereas nonepithelial Wnt signals could provide a secondary physiological source of Wnt. © 2012 AGA Institute.


Koo B.-K.,Hubrecht Institute for Developmental Biology and Stem Cell Research | Koo B.-K.,University of Cambridge | Van Es J.H.,Hubrecht Institute for Developmental Biology and Stem Cell Research | Van Den Born M.,Hubrecht Institute for Developmental Biology and Stem Cell Research | Clevers H.,Hubrecht Institute for Developmental Biology and Stem Cell Research
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

Rnf43 (RING finger protein 43) and Znrf3 (zinc/RING finger protein 3) (RZ) are two closely related transmembrane E3 ligases, encoded by Wnt target genes, that remove surface Wnt (wingless-int) receptors. The two genes are mutated in various human cancers. Such tumors are predicted to be hypersensitive to, yet still depend on, secreted Wnts. We previously showed that mutation of RZ in the intestine yields rapidly growing adenomas containing LGR5+ (leucine-rich repeat-containing G-protein coupled receptor 5) stem cells and Wnt3-producing Paneth cells. We now show that removal of Paneth cells by Math1 mutation inhibits RZ-/- tumor formation. Similarly, deletion of Wnt3 inhibits tumorigenesis. Treatment of mice carrying RZ-/- intestinal neoplasia with a small molecule Wnt secretion inhibitor (porcupine inhibitor C59) strongly inhibited growth, whereas adjacent normal crypts remained intact. These results establish that paracrine Wnt secretion is an essential driver of RZ-/- tumor growth and imply that a therapeutic window exists for the use of porcupine inhibitors for RZ-mutant cancers. © 2015, National Academy of Sciences. All rights reserved.


Oldenburg J.,Hubrecht Institute for Developmental Biology and Stem Cell Research | De Rooij J.,Hubrecht Institute for Developmental Biology and Stem Cell Research
Cell and Tissue Research | Year: 2014

The integrity of the endothelial barrier is controlled by the combined action of chemical and mechanical signaling systems. Permeability-regulating factors signal through small GTPases to regulate the architecture of the cytoskeleton and this has a strong impact on the morphology and stability of VE-cadherin-based cell-cell junctions. The details of how structural and mechanical properties of the actin cytoskeleton influence cell-cell adhesion and how this impacts the dynamic regulation of the endothelial barrier, are beginning to be elucidated. In this review, we discuss the physical and regulatory interactions between the VE-cadherin complex and the actomysoin cytoskeleton, as they are the main determinants of cell-cell adhesion and the mechanical architecture of the cytoskeleton. We discuss, based on recent in vitro data, how a balance between Linear Adherens Junctions, paralleled by cortical actin bundles and Focal Adherens Junctions, connected to radial action bundles, determines endothelial barrier function. We discuss how small GTPases control this balance by regulating the spatial organization and mechanics of actomyosin. We propose a hypothetical model of how biochemical and mechanical signals cooperate locally, at the actomyosin-adhesion interface to open and re-seal the barrier in a rapid and controlled manner. © 2014 Springer-Verlag Berlin Heidelberg.


Sachs N.,Hubrecht Institute for Developmental Biology and Stem Cell Research | Clevers H.,Hubrecht Institute for Developmental Biology and Stem Cell Research
Current Opinion in Genetics and Development | Year: 2014

Preclinical models of cancer are essential for a basic understanding of cancer biology and its translation into efficient treatment options for affected patients. Cancer cell lines and xenografts derived directly from primary human tumors have proven very valuable in fundamental oncology research and anticancer drug discovery. Both models inherently comprise advantages and caveats that have to be accounted for. We will outline in these and discuss primary patient derived organoids as third preclinical cancer model. We propose that cancer organoids could potentially fill the gap between simple cancer cell lines suitable for high-throughput screens and complicated, but physiologically relevant xenografts. The resulting applications for cancer organoids range from basic research to drug screens and patient stratification. © 2013 Elsevier Ltd.


van Es J.H.,Hubrecht Institute for Developmental Biology and Stem Cell Research
Nature communications | Year: 2010

Intestinal cells are constantly produced from a stem cell reservoir that gives rise to proliferating transient amplifying cells, which subsequently differentiate into one of the four principal cell types. Signalling pathways, including the Notch signalling pathway, coordinate these differentiation processes and their deregulation may cause cancer. Pharmacological inhibition through γ-secretase inhibitors or genetic inactivation of the Notch signalling pathway results in the complete loss of proliferating crypt progenitors due to their conversion into post-mitotic goblet cells. The basic helix-loop-helix transcription factor Math1 is essential for intestinal secretory cell differentiation. Because of the critical roles of both Math1 and Notch signalling in intestinal homeostasis and neoplastic transformation, we sought to determine the genetic hierarchy regulating the differentiation of intestinal stem cells into secretory cells. In this paper, we demonstrate that the conversion of intestinal stem cells into goblet cells upon inhibition of the Notch signalling pathway requires Math1.


de Lau W.B.M.,Hubrecht Institute for Developmental Biology and Stem Cell Research | Snel B.,Theoretical Biology and Bioinformatics | Clevers H.C.,Hubrecht Institute for Developmental Biology and Stem Cell Research
Genome Biology | Year: 2012

The four vertebrate R-spondin proteins are secreted agonists of the canonical Wnt/β-catenin signaling pathway. These proteins are approximately 35 kDa, and are characterized by two amino-terminal furin-like repeats, which are necessary and sufficient for Wnt signal potentiation, and a thrombospondin domain situated more towards the carboxyl terminus that can bind matrix glycosaminoglycans and/or proteoglycans. Although R-spondins are unable to initiate Wnt signaling, they can potently enhance responses to low-dose Wnt proteins. In humans, rare disruptions of the gene encoding R-spondin1 cause a syndrome of XX sex reversal (phenotypic male), palmoplantar keratosis (a thickening of the palms and soles caused by excess keratin formation) and predisposition to squamous cell carcinoma of the skin. Mutations in the gene encoding R-spondin4 cause anonychia (absence or hypoplasia of nails on fingers and toes). Recently, leucine-rich repeat-containing G-protein-coupled receptor (Lgr)4, Lgr5 and Lgr6, three closely related orphans of the leucine-rich repeat family of G-protein-coupled receptors, have been identified as receptors for R-spondins. Lgr5 and Lgr6 are markers for adult stem cells. Because R-spondins are potent stimulators of adult stem cell proliferation in vivo and in vitro, these findings might guide the therapeutic use of R-spondins in regenerative medicine. © 2012 BioMed Central Ltd.

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