Communications cellulaires et tissulaires au cours de l’organogenèse: approches innovantes / Cell- and tissue communication during organogenesis

Séminaire FSER organisé par Yoshiko Takahashi (Kyoto University, Japan) et Christof Niehrs (IMB, Mainz, Germany) du 21 au 26 septembre 2015

Participants

Igor Adameyko, Alexander Aulehla, Marianne Bronner-Hansen, Hironobu Fujiwara, Jérôme Gros, Chenghua Gu, Thomas Kornberg, Erina Kuranaga, Moisés Mallo Perez, Roberto Mayor, Christof Niehrs, Angela Nieto, Olivier Pourquié, Daisuke Saito, Kate Storey, Yoshiko Takahashi, Hiroyuki Takeda

—

Résumé

Chez les animaux, l’organogenèse décrit le processus durant lequel les organes internes se forment à partir de trois couches germinales : l’ectoderme, le mésoderme et l’endoderme. La communication cellulaire joue un rôle central dans ce processus. Les cellules s’instruisent mutuellement sur leur position pour réguler la division cellulaire, leur mouvement et leur différenciation. Des progrès considérables ont été accomplis dans l’identification et la caractérisation des médiateurs moléculaires de cette communication cellulaire que sont facteurs de croissance, récepteurs et molécules d’adhésion cellulaire, ainsi que dans celle des molécules intracellulaires qui transmettent les signaux vers le cytoplasme et le noyau cellulaire. Ce séminaire a réuni aux Treilles des chercheurs internationaux travaillant sur différents systèmes de modèles animaux et différents organes. Ils ont présenté leurs derniers résultats, souvent inédits, et les ont discutés en profondeur. Deux des 17 participants étaient de jeunes chercheurs en provenance du Japon qui ont présenté leur travail en mettant l’accent sur les mécanismes de la morphogenèse. Le système nerveux, et son développement, a été l’organe le plus discuté. Les thèmes principaux abordés ont été ceux des mécanismes cellulaires du développement impliquant des structures cellulaires tels que les cytonèmes et les cils primaires, ou des processus cellulaires tels que l’endocytose et la polarisation des cellules.

Abstract

During animal development organogenesis is the process when the internal organs are formed from the three germ layers ectoderm, mesoderm and endoderm. In this process cell communication plays a pivotal role, they instruct each other about their position to regulate cell division, cell movement and cell differentiation. Enormous progress has been made in understanding the molecules which mediate cell communication, including growth factors, receptors, cell adhesion molecules as well as components in cells which transmit the signals to the cytoplasm and the cell nucleus. This Les Treilles Seminar event brought together 17 researchers (6 female, 2 junior) from Europe, Asia and North America, who are working on a variety of animal model systems and developing organs and discussed their latest results, often unpublished. The central topics included morphogenesis, neural development, and cell biological mechanisms underlying cell communications.

—

Presentations

Yoshiko Takahashi, as the chief organizer, opened the symposium by explaining the aim of this conference. This was followed by the presentation of her recent studies. She described the mechanisms of tail formation in vertebrates with a particular focus on the secondary neurulation (SN) seen in the caudal body, a different type of neurulation from that seen in the anterior body. SN involves stem cell-like behavior of precursor cells. She discussed the developmental lineage of SN precursors with a set of evidence that a majority of neural precursors in the caudal body are neural-fated with a limited contribution of neural-mesodermal common precursors.

Daisuke Saito described the mechanisms of avian primordial germ cell (PGC) migration. Avian PGCs migrate via blood vessels. He showed that after translocation by blood flow, PGCs are trapped by the capillaries, which is followed by extravasation of the cells. He proposes that the stiffness of PGCs is crucial for the trapping and extravasation. Indeed, a PGC is much stiffer than other types of cells, and this stiffness is mediated by cortical actin.

Marianne Bronner presented studies on gene regulatory interactions underlying neural crest formation, using the avian embryo as a model. Her lab has identified several enhancers that mediate expression of neural crest specifier genes like FoxD3 and Sox10. Interestingly, they uncovered separate enhancers that drive expression at cranial versus trunk axial levels. These enhancers enable isolation of pure populations of neural crest cells for transcriptome analysis. She described how this information can be used to build a cranial-specific gene regulatory circuit for use in reprogramming neural crest cells.

Moises Mallo addressed the question of what makes some vertebrates, like snakes, have very long organ-filled trunks, while others like lizards, despite also having very long bodies, have rather short organ-containing trunks and long tails instead. Using the mouse as the experimental system he dissected the molecular mechanisms responsible for this remarkable body shape variability. In particular, he showed how genetic-mediated alteration of those molecular processes impacted the anatomy of the mouse embryo.

Igor Adameyko applied a combination of advanced tomography and image analysis methods to analyze skull shape and morphogenesis in mice. The results imply that specific molecular signals involving BMP action control allocation, polarization and expansion of individual skeletogenic clones and, through this process, provide precise sculpting and scaling up cartilaginous and bony structures in development and during regeneration.

Roberto Mayor described how directional migration of neural crest cells is controlled by a combination of cellular activities, which include contact inhibition of locomotion and co-attraction. Simulations based on mathematical modeling were compared with cell migration in vivo and in vitro. The role of complement factors in neural crest migration and during gastrulation was also discussed.

Chenghua Gu described their recent findings of a key molecular regulator, Mfsd2a, and its novel mechanism underlying the formation and function of the blood-brain barrier. Mfsd2a controls BBB integrity by inhibiting transcytosis, highlighting vesicular trafficking as a major mechanism for BBB function, which supplements nearly exclusive previous emphasis on tight junctions. They also identified a list of candidate genes that provide new avenues toward a comprehensive understanding of the mechanisms controlling BBB formation and function. This comprehensive understanding may enable strategies to manipulate the BBB for the purposes of drug delivery and neurological disease treatment.

Erina Kuranaga proposed the new scenario for directional epithelial cell movement that is different from the conventional guidance-mediated cellular movement, based on Drosophila genitalia rotation in which epithelial tissue rotates clockwise around the genitalia. In the scenario, the individual LR asymmetry of epithelial cells and polarized cell intercalation are sufficient to organize the directional flow of epithelial tissue.

Kate Storey spoke about a new form of cell sub-division, apical abscission, which mediates release of new born neurons from the ventricular surface of the spinal cord. This requires actin-myosin contraction and Storey presented new data uncovering accompanying microtubule dynamics, their requirement for apical abscission and their dependence on actin-myosin contraction. Apical abscission also disassembles the primary cilium, which transduces sonic hedgehog signaling. Storey described experiments that address the consequence of the abscission process for signaling through this mitogenic pathway. These suggest that cilium disassembly help to ensure cell cycle exit and provides a period during which the cell is re-configured as a differentiating post-mitotic cell.

Hiroyuki Takeda describes the spontaneous Medaka mutant Double anal fin, which exhibits a mirror-image duplication of the ventral half across the lateral midline from larva to adult. He also demonstrated the cellular mechanism that establishes the D-V boundary by a new group of cells in somites, called boundary cells.

Angela Nieto discussed how epithelial plasticity operates during embryonic development and cancer progression to first promote cell delamination and migration and later ensure cell colonization for the formation of organs and metastatic outgrowths. As epithelial homeostasis is crucial to maintain tissue architecture, it needs to be tightly regulated, and she presented data to suggest that evolution may have favored mechanisms that attenuate the epithelial to mesenchymal transition triggered by some EMT inducers.

Tom Kornberg described studies showing that in Drosophila, signaling by Dpp, Hedgehog, Wingless, FGF and Delta-Notch is dependent on cell-cell contacts made by specialized filopodia called cytonemes. Studies of the process by which cytonemes navigate to their targets were also described. These studies show that cytonemes depend on integrin signaling in the cytoneme-producing cells and on functions encoded by the PCP genes prickled and Van Gogh and on the HSPG genes Dally and Dally-like in the cells over which the cytonemes extend.

Hironoubu Fujiwara described how cellular microenvironment is spatiotemporally specialized and it influences the hair follicle morphogenesis, focusing on the extracellular matrix heterogeneity. He also talked about his new imaging system that visualizes the induction process of hair follicle stem cells at single cell resolution.

Olivier Pourquie reviewed the role of retinoic acid (RA) signaling during somitogenesis, where it is important for maintaining left-right symmetric patterning. Consequently RA signaling mutants show somite symmetry defects. He described a novel RA receptor complex, WHHERE, involving HADAC1 and WDR5, highlighting the role of chromatin regulation in somitogenesis.

Alexander Aulehla addressed the role of Notch and Wnt-signalling oscillations in the process of mesoderm segmentation and scaling in mouse embryos. Using a combination of novel in vitro assays with real-time imaging quantifications of customized reporter lines, he presented findings addressing the role of coordinated oscillations in encoding both temporal and also spatial information during segmentation. His presentation ended with a discussion on the working principles underlying the origin of periodic spatiotemporal wave patterns.

Jerome Gros presented progress on efforts aiming at elevating quails to the rank of animal genetic model, as well as results on the cellular basis of gastrulation movements in chick. Using live imaging and various functional assays, he showed that cell division plays a predominant role in the generation of these movements by inducing massive rearrangements of cells.

Christof Niehrs discussed canonical Wnt signaling, a pathway thought to regulate cell behavior mainly by inducing b-catenin-dependent transcription of target genes. In proliferating cells Wnt signaling peaks in the G2/M phase of the cell cycle, but the significance of this ‘mitotic Wnt signaling’ is unclear. He introduced Wnt-dependent stabilization of proteins (Wnt/STOP), which is independent of b-catenin and peaks during mitosis. Wnt/STOP plays a critical role in protecting proteins from GSK3-dependent polyubiquitination and degradation. Wnt/STOP signaling increases cellular protein levels and cell size. Wnt/STOP rather than b-catenin signaling is the dominant mode of Wnt signaling in several cancer cell lines and gametes. He also summed up the conference as the co-organizer.

Two general discussion sessions were held, one on the use of antisense Morpholino oligonucleotides, where it was concluded that they remain a powerful tool in developmental biology even in the age of CRISPR/CAS9 mediated genome editing. The other session discussed the state of the field of Developmental Biology with the revolution in stem cell biology and other adjacent fields, and the consequences for publishing and funding. It was concluded that modern technologies notably in imaging and large scale sequencing offer vast new opportunities to tackle fundamental questions in Developmental Biology.

---

---