ORCID Profile
0000-0002-8583-1721
Current Organisation
KU Leuven
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Publisher: The Company of Biologists
Date: 11-2014
DOI: 10.1242/DEV.107425
Abstract: During the early steps of head development, ectodermal patterning leads to the emergence of distinct non-neural and neural progenitor cells. The induction of the preplacodal ectoderm and the neural crest depends on well-studied signalling interactions between the non-neural ectoderm fated to become epidermis and the prospective neural plate. By contrast, the involvement of the non-neural ectoderm in the morphogenetic events leading to the development and patterning of the central nervous system has been studied less extensively. Here, we show that the removal of the rostral non-neural ectoderm abutting the prospective neural plate at late gastrulation stage leads, in mouse and chick embryos, to morphological defects in forebrain and craniofacial tissues. In particular, this ablation compromises the development of the telencephalon without affecting that of the diencephalon. Further investigations of ablated mouse embryos established that signalling centres crucial for forebrain regionalization, namely the axial mesendoderm and the anterior neural ridge, form normally. Moreover, changes in cell death or cell proliferation could not explain the specific loss of telencephalic tissue. Finally, we provide evidence that the removal of rostral tissues triggers misregulation of the BMP, WNT and FGF signalling pathways that may affect telencephalon development. This study opens new perspectives on the role of the neural/non-neural interface and reveals its functional relevance across higher vertebrates.
Publisher: Proceedings of the National Academy of Sciences
Date: 21-01-2005
Abstract: γ-Secretase is the protease responsible for amyloid β peptide release and is needed for Notch, N-Cadherin, and possibly other signaling pathways. The protease complex consists of at least four subunits, i.e., Presenilin, Aph1, Pen2, and Nicastrin. Two different genes encode Aph1A and Aph1B in man. A duplication of Aph1B in rodents has given rise to a third gene, Aph1C . Different mixes of γ-secretase subunits assemble in at least four human and six rodent complexes but it is not known whether they have different activities in vivo . We report here the inactivation of the three Aph1 genes in mice. Aph1A –/– embryos show a lethal phenotype characterized by angiogenesis defects in the yolk sac, neuronal tube malformations, and mild somitogenesis defects. Aph1B –/– or C –/– or the combined Aph1BC –/– mice (which can be considered as a model for total Aph1B loss in human) survive into adulthood. However, Aph1BC –/– deficiency causes a mild but significant reduction in amyloid β percursor protein processing in selective regions of the adult brain. We conclude that the biochemical and physiological repercussions of genetically reducing γ-secretase activity via the different Aph1 components are quite ergent and tissue specific. Our work provides in vivo evidence for the concept that different γ-secretase complexes may exert different biological functions. In the context of Alzheimer's disease therapy, this implies the theoretical possibility that targeting specific γ-secretase subunit combinations could yield less toxic drugs than the currently available general inhibitors of γ-secretase activity.
Publisher: The Company of Biologists
Date: 15-09-2012
DOI: 10.1242/DEV.075465
Abstract: The strength and spatiotemporal activity of Nodal signaling is tightly controlled in early implantation mouse embryos, including by autoregulation and feedback loops, and involves secreted and intracellular antagonists. These control mechanisms, which are established at the extra-embryonic/embryonic interfaces, are essential for anterior-posterior patterning of the epiblast and correct positioning of the primitive streak. Formation of an ectopic primitive streak, or streak expansion, has previously been reported in mutants lacking antagonists that target Nodal signaling. Here, we demonstrate that loss-of-function of a major bone morphogenetic protein (BMP) effector, Smad5, results in formation of an ectopic primitive streak-like structure in mutant amnion accompanied by ectopic Nodal expression. This suggests that BMP/Smad5 signaling contributes to negative regulation of Nodal. In cultured cells, we find that BMP-activated Smad5 antagonizes Nodal signaling by interfering with the Nodal-Smad2/4-Foxh1 autoregulatory pathway through the formation of an unusual BMP4-induced Smad complex containing Smad2 and Smad5. Quantitative expression analysis supports that ectopic Nodal expression in the Smad5 mutant amnion is induced by the Nodal autoregulatory loop and a slow positive-feedback loop. The latter involves BMP4 signaling and also induction of ectopic Wnt3. Ectopic activation of these Nodal feedback loops in the Smad5 mutant amnion results in the eventual formation of an ectopic primitive streak-like structure. We conclude that antagonism of Nodal signaling by BMP/Smad5 signaling prevents primitive streak formation in the amnion of normal mouse embryos.
Publisher: The Company of Biologists
Date: 2016
DOI: 10.1242/DEV.134171
Abstract: Thyroid follicles, the functional units of the thyroid gland, are delineated by a monolayer of thyrocytes resting on a continuous basement membrane. Developmental mechanisms whereby follicles are formed by reorganization of a non-structured mass of non-polarized epithelial cells (folliculogenesis) largely unknown. Here we show that assembly of the epithelial basement membrane is critical for folliculogenesis and is controlled by endothelial cell invasion and by BMP-Smad signaling in thyrocytes. Thyroid-specific double Smad1 and Smad5 knockout mice (Smad1/5dKO) displayed growth retardation, hypothyroidism and defective follicular architecture. In Smad1/5dKO embryonic thyroids, epithelial cells remained associated in large clusters and formed small follicles. Although similar follicular defects are found in VegfaKO thyroids, Smad1/5dKO thyroids had normal endothelial cell density yet impaired endothelial differentiation. Interestingly, both VegfaKO and Smad1/5dKO thyroids displayed impaired basement membrane assembly. Furthemore, conditioned medium (CM) from embryonic endothelial progenitor cells (eEPC) rescued the folliculogenic defects of both Smad1/5dKO and VegfaKO thyroids. Laminin α1β1γ1, abundantly released by eEPC into CM, was critically required for folliculogenesis. Thus, epithelial Smad signaling and endothelial cell invasion promote folliculogenesis via assembly of the basement membrane.
Publisher: Hindawi Limited
Date: 2012
DOI: 10.1155/2012/987185
Abstract: Tracing the precise developmental origin of amnion and amnion-derived stem cells is still challenging and depends chiefly on analyzing powerful genetic model amniotes like mouse. Profound understanding of the fundamental differences in amnion development in both the disc-shaped primate and human embryo and the cup-shaped mouse embryo is pivotal in particular when s ling amniotic membrane from nonprimate species for isolating candidate amniotic stem cells. The availability of molecular marker genes that are specifically expressed in the amniotic membrane and not in other extraembryonic membranes would be instrumental to validate unequivocally the starting material under investigation. So far such amniotic markers have not been reported. We postulated that bone morphogenetic protein (BMP) target genes are putative amniotic membrane markers mainly because deficiency in one of several components of the BMP signaling cascade in mice has been documented to result in defective development of the early amnion. Comparative gene expression analysis of acknowledged target genes for BMP in different extraembryonic tissues, combined with in situ hybridization, identified Periostin (Postn) mRNA enrichment in amnion throughout gestation. In addition, we identify and propose a combination of markers as transcriptional signature for the different extraembryonic tissues in mouse.
Publisher: The Company of Biologists
Date: 2018
DOI: 10.1242/DEV.157222
Abstract: Upon gastrulation, the mammalian conceptus transforms rapidly from a simple bilayer into a multi-layered embryo enveloped by its extraembryonic membranes. Impaired development of the amnion, the innermost membrane, causes major malformations. To clarify the origin of the mouse amnion, we used single cell-labelling and clonal analysis. We identified four clone types with distinct clonal growth patterns in amniotic ectoderm (AmEc). Two main types have progenitors in extreme proximal-anterior epiblast. Early descendants initiate and expand AmEc posteriorly, while descendants of cells remaining anteriorly later expand AmEc from its anterior side. Amniogenesis is abnormal in embryos deficient in the BMP signalling effector SMAD5, with delayed closure of the proamniotic canal, and aberrant amnion and folding morphogenesis. Transcriptomics of in idual Smad5 mutant amnions isolated before visible malformations, and tetraploid chimera analysis, revealed two amnion defect sets. We attribute them to impairment of progenitors of the two main cell populations in AmEc and to compromised cuboidal-to-squamous transition of anterior AmEc. In both cases, SMAD5 is critical for expanding AmEc rapidly into a stretchable squamous sheet to accommodate exocoelom expansion, axial growth and folding morphogenesis.
Publisher: The Company of Biologists
Date: 08-2018
DOI: 10.1242/DEV.169722
No related grants have been discovered for An Zwijsen.