The ability of tissues and cells to move and rearrange is central to a broad range of diverse biological processes such as tissue remodeling and rearrangement in embryogenesis, cell migration in wound healing, or cancer progression. These processes are linked to a solidlike to fluid-like transition, also known as unjamming transition, a not rigorously defined framework that describes switching between a stable, resting state and an active, moving state. Various mechanisms, that is, proliferation and motility, are critical drivers for the (un) jamming transition on the cellular scale. However, beyond the scope of these fundamental mechanisms of cells, a unifying understanding remains to be established. During embryogenesis, the proliferation rate of cells is high, and the number density is continuously increasing, which indicates number-density-driven jamming. In contrast, cells have to unjam in tissues that are already densely packed during tumor progression, pointing toward a shape-driven unjamming transition. Here, we review recent investigations of jamming transitions during embryogenesis and cancer progression and pursue the question of how they might be interlinked. We discuss the role of density and shape during the jamming transition and the different biological factors driving it.

Selon la tradition, Samuel de Champlain aurait retenu le site de Québec pour ses qualités défensives. Mais se pourrait-il qu'à défaut de comprendre Champlain, la tradition ait préféré questionner la nature au lieu de questionner le fondateur? Cette question constitue notre point de départ. Notre projet consiste à comprendre Québec à l'aune d'une morphogenèse traduisant une mobilisation des acteurs par les formes sensibles des paysages, préalablement investies de valeurs. La fondation de Québec aurait été le fait d'un investissement de représentations symboliques auxquelles le promontoire aurait fait écho. C'est que depuis la Renaissance, la localisation de certains acteurs serait influencée par une coïncidence entre des formes symboliques (idéaux, modèles...) et les images mentales que peuvent suggérer les formes des paysages. Dans ce processus, les artistes auraient la capacité de nous révéler ces coïncidences. Dans cette optique, quatre acteurs auraient lourdement infléchie la morphogenèse de Québec. Champlain, malgré ses prétentions, aurait finalement été contraint d'occuper une position attribuée, son «choix» pour Québec relevant notamment d'une coïncidence entre l'intuition qu'il pouvait avoir de la géopolitique amérindienne et des formes paysagères pouvant suggérer les discontinuités découlant de cette géopolitique. Dans le regard de Montmagny, le promontoire de Québec aurait fait écho à la posture que s'attribuait alors le sujet baroque. Le sujet aurait cherché à exprimer son unicité en s'associant avec les saillances du paysage. Mais au même moment, d'autres acteurs baroques — les communautés religieuses — auraient elles aussi été mobilisées par le promontoire de Québec. Une mimesis d'appropriation aurait été amplifiée par un paysage pouvant suggérer le rang social de ces acteurs. De cette rivalité devait émerger l'organisation axiale de Québec. Cette axialité a eu et a encore, une forte incidence sur le devenir de Québec. L'organisation du domaine bâti de Québec — des faubourgs enserrant un centre — aurait évoqué l'individualisme romantique, incitant les bourgeoisies à vouloir occuper le bourg fortifié. Modernes, elles voulaient détruire les murs de Québec. Or, Lord Dufferin les forçait à conserver ces derniers. La morphogenèse de Québec prenait une nouvelle tangente sous l'influence d'une confusion entre un idéal individualiste, l'organisation du paysage de Québec et une position centrale qui changeait de valeur. Les bourgeoisies se aisaient prendre dans un «piège paysager». Depuis lors, la morphogenèse de Québec ne ferait que s'inscrire à l'intérieur du lourd héritage de la «vieille capitale», au détriment de quartiers entiers. Aujourd'hui, nous pouvons constater que certains espaces, sous l'influence d'idéaux spécifiques, sont l'objets d'investissements de valeurs. Le bourg fortifié, dans la foulée de son classement, est l'objet d'une valorisation par des acteurs inscrits dans des trajectoires longues. Il est de ce fait de plus en plus un espace vide. Aussi, sous l'influence des discours environnementaux, le bassin de Québec serait en train d'émerger comme espace attractif, et ce, en concurrence avec les investissements récents dans le nouveau centre-ville. / According to tradition, the site for the construction of Québec was chosen by Samuel de Champlain for its defensive properties. Yet, while having no insight of the founder’s intentions, could it be that the above tradition preferred to investigate nature instead of investigating Champlain’s motives? This question constitutes the starting point of this research endeavor. It aims at understanding Québec from the very start of its morphogenesis resulting from a succession of actors influenced by the perceived landscape forms pre-invested with human values. Hence, the founding of Québec would have been the result of representation inputs of a symbolic nature to which echoed its promontary, considering that since Renaissance the location of certain actors could have been determined through the coincidence between symbolic forms ( ideals, models...) and the mental images as generated by the forms of the landscape. In this process, artists tend to unveil these coincidences. In that perspective, four actors have strongly inflected the morphogenesis of Québec. Champlain, notwithstanding his claims, would have been constrained to occupy a designated position, his «choice» for Québec resulting from a coincidence between his possible intuition of the ameridian geopolitics and the landscape forms suggesting the potential discontinuities created by this geopolitics. As seen by Montmagny, the Québec promontory evoqued the posture to which the Baroque individual pretended: his tendency to express his wholesomeness by his association with the stricking features of the landscape. But at the same time, other Baroque actors — the religious communities — invested the Québec promontory: an appropriative mimesis would have been amplified by a landscape able to suggest the social position of these actors. From this rivalry resulted the axial organisation of Québec which had and still has a strong incidence upon the spatial evolution of the agglomeration. The organization of the built form of Québec — faubourgs enclosing a centre — would have evoqued the romantic individualism, encouraging the (modern) bourgeoisies to occupy the fortified bourg; they wanted to destroy its walls, while Lord Dufferin insisted in conserving them. From then on, the morphogenesis of Québec took a new direction under the influence of a confusion between the individualistic ideal, the structured landscape of Québec and a central position undergoing a value change. Hence, the bourgeoisies were caught into a «landscape trap». Since then, the morphogenesis of Québec is still submitted to the constraining legacy of the «old Québec», creating prejudice to surrounding neighbourhoods. As a result, one can ascertain that today some portions of the agglomeration, under the influence of specific ideals, are subjected to new value investments. The fortified bourg, following its designation as a Heritage precinct (UNESCO), is subjected to a valorization process by actors set in long term trajectories; hence, it more and more becomes an “empty place”. Moreover, influenced by the environmental discourse, the walled City and its harbour seem to emerge as a space of attraction, this being in competition with the recent investments in the new CBD.

Transient Receptor Potential channels (TRP) are a superfamily of cationic specific ionchannels that are regulated by various stimuli such as temperature, pH, mechanical stress, ligandsand ion concentration. The role of TRP channels in disease states such as autosomal dominantpolycystic kidney disease, cancer metastasis, and developmental defects lend credence to thebelief that they play an important part in epithelial morphogenesis events. The development ofsomites, neural tube closure and migration of neural crest cells to form things such as the faceand heart is a good developmental model for the aforementioned cellular processes. We haveshown that TRP channels can be found in the developing ectoderm, hindbrain, and heart and thatthe inhibition of TRP channels in a developing embryo results in phenotypes suggestingperturbation of cellular remodeling processes. This leads to the question of the specific role ofTRP channels in the epithelial mesenchymal transition and remodeling in developing chickembryos.

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During animal development numerous organs with functions ranging from fluid transport to signal propagation develop into highly branched shapes and forms. To ensure organ function, the formation of their geometrical and topological as well as size-dependent properties is crucial. For example, organ geometry serves to maximize exchange area with its surroundings and organ topology controls the response to fluctuations and damage. Most importantly, organ size and proportion need to scale throughout animal growth to meet the demands of increasing body size. However, how organ geometry and topology are established and scaled in a self-organized manner, remains poorly understood. In this thesis, we present a novel theoretical framework to study the self-organized growth and scaling of branched organs. In this framework, we represent the organ outline by an infinitely thin interface and consider morphogen-controlled interface evolution in growing domains. We demonstrate that an instability in interface motion can lead to the self-organized formation of complex branched morphologies and show how the interplay between interface motion, morphogen dynamics, and domain growth controls the geometrical, topological, and size-dependent properties of the resulting structures. To understand the formation of branched structures from instabilities in morphogen-controlled interface growth, we first consider a range of different interface growth scenarios in non-growing domains. In a first approach, we present a stochastic lattice model with interface growth driven by a morphogen concentration gradient. We find a range of branched morphologies extending from self-similar fractal structures to almost circular structures with only a few branches depending on the morphogen gradient length scale. We present the Euler characteristic as an example of a topological invariant and employ it to introduce topological constraints into interface growth, leading to the formation of tree-like structures. In a second approach, we study a continuum model for morphogen-controlled interface growth. In this model, the interface has a constant tendency to grow and is inhibited by morphogen concentration. Additionally, we take into account a curvature dependency of interface growth, which leads to an effective stabilization of interface motion at small length scales. We identify branch distance and thickness as key morphological properties and discuss their regulation. We relate branch distance regulation to the interplay of destabilization from morphogen inhibition and stabilization from the curvature dependency of interface growth and explain branch thickness regulation in terms of mutual branch inhibition. By considering interface instability in different scenarios, we overall demonstrate the robustness of our approach. Finally, we apply our theoretical framework to study the branching morphogenesis of the planarian gut. The planarian gut is a highly branched organ that spans the entire organism and is responsible for the delivery of nutrients to the planarian body. Planarians undergo massive body size changes of more than one order of magnitude in organism length and thus constitute an ideal model organism to study the growth and scaling of branched organs. We reconsider our continuum model and include novel features needed to account for the organization of the planarian gut. We take into account external guiding cues that alter the orientation of branches and, most importantly, consider branching morphogenesis in a growing domain. We demonstrate that our model can account for the geometrical and topological properties of the gut and show that gut scaling can arise from to the interplay of branch growth and organism growth. Overall, we present a novel theoretical framework to study the growth and scaling of branched organs. In this framework, we demonstrate the self-organized formation of branched morphologies from instabilities in morphogen-controlled interface growth and show how the interplay of interface motion, morphogen dynamics, and system size determine geometry, topology, and size-dependent properties of the resulting structures.

The aim of this thesis was to investigate morphogenesis in the fruit fly Drosophila melanogaster using three in vitro tissue culture systems. Primary embryonic cultures derived from Drosophila melanogaster were used to study the effect of the moulting hormone ecdysone on cells in culture. The hypothesis was that the effect of ecdysone on these primary embryonic cells would parallel events which occur during metamorphosis in vivo and therefore the primary embryonic cultures could be used as an ‘in vitro’ model system. Transgenic fly lines expressing GFP were used to visualise and identify specific cell types and it was shown that cells in primary embryonic cultures respond to ecdysone morphologically. However due to the variability of cultures it was concluded that this culture system was not suitable for use as a model system. As defined cell types were observed the development of a protocol suitable for use with the primary embryonic culture system using dsRNA in order to demonstrate RNA interference was undertaken. Although this was unsuccessful, as cells in the primary embryonic cultures appeared to be resistant to dsRNA, some technical avenues remain to be explored. The Drosophila melanogaster cell line, Clone 8+, was used to investigate cell adhesion in tissue culture. Statistical analyses were carried out and it was established that derivatives of the parent cell line, Clone 8+, showed differential adhesion and proliferation characteristics. Analysis of microarray data was carried out in order to identify genes which may be responsible for the loss of cell adhesion in Clone 8+ cell lines and the potential roles of these genes in adhesion were discussed. A gene of interest, glutactin, was identified which may be responsible for loss of cell adhesion. Antibody staining was used to establish the expression of the protein glutactin in the Clone 8+ cell lines. The expression of glutactin suggested that the Clone 8+ cell line had maintained properties of the wing disc epithelial cell-type and disruption of cell polarity was considered as a possible mechanism. It was shown that f-actin colocalised with glutactin and the role of the cytoskeleton in glutactin secretion was discussed. It was concluded that glutactin was not responsible for loss of cell adhesion in the Clone 8+ cell lines. Further analysis of the microarray data revealed potential genes that could be responsible for the loss of cell polarity in the Clone 8+ cell lines and the possibility of cellular senescence was considered. It was hypothesised that the properties of adhesion and proliferation related to their ‘in vitro’ age. In the final investigation the movement of epithelial cells in Drosophila melanogaster third instar larval imaginal discs during morphogenesis was investigated. Firstly a lumen was identified in fixed imaginal disc tissue in association with cells expressing f-actin. This result was discussed in relation to the process of dorsal closure and wound healing. Further investigations involved live imaging of the dynamic process of evagination in the imaginal wing disc using transgenic flies expressing moesin-GFP. It was concluded that the lumen was not associated with the process of wound healing and it was concluded that the lumen appeared to be the mechanism directing peripodial epithelium contraction during morphogenesis of the imaginal wing disc. Dorsal closure and the process of invagination in relation to morphogenesis of the imaginal wing disc were discussed.

Konjac glucomannan (KGM), the main biologically active constituent of konjac flour extracted from corms of Amorphophallus konjac (konjac), can be used to prepare functional foods and may also have potential as a pharmaceutical product to combat obesity. The current study employed three experimental approaches to study the biology and chemistry of konjac, namely (1) glasshouse experiments to study the morphogenesis, growth and productivity of konjac plants, (2) a histological and immunocytochemical investigation of the localisation and developmental regulation of the deposition and metabolism of KGM in developing corm tissues, and (3) a comparative study of methodologies for the extraction and analysis of KGM. The current data demonstrated a morphological and functional separation between the ventral and dorsal regions of corms. The ventral region appeared to function as a source during the initial period of shoot development, while the dorsal region appeared to operate as a sink after the development of mature canopy. Once the corm reached maturity, both an inflorescence and a leaf were produced within a single season. It has also been demonstrated that the age of the ‘mother’ corm is an important factor affecting the quality of offsets produced. An anti-mannan antiserum detected a temporally regulated pattern of mannan epitope production within glucomannan idioblasts in developing corm tissues, with increased expression as the corm approached maturity/dormancy. The current observations also suggest that the mobilization of KGM initiates at the periphery of the corm and proceeds inwards towards the centre of the corm. Compositional analysis showed that the purified konjac flour (PKF) produced using a modified extraction procedure contained 92% glucomannan, with a weight average molecular weight (Mw), polydispersity index (PDI) and degree of acetylation (DA) of 9.5 ± 0.6 x 105 gmol-1, 1.2 and 2.8 wt. %. These data, plus Fourier-transform infrared spectral (FTIR) and zero shear viscosity analyses of the extract (PKF) were all consistent with the literature. Comparison of three existing methodologies for the quantitative analysis of the KGM content, namely 3,5-dinitrosalicylic acid (3,5-DNS), phenol-sulphuric acid and enzymatic colorimetric assays; indicated that the 3,5-DNS colorimetric assay was the most reproducible and accurate method, with a linear correlation coefficient of 0.997 and recoveries between 97% and 103% across three spiking levels of starch. In summary, this study has provided a better understanding of aspects of the biology and cultivation of A. konjac and has also produced methodologies which can be used as the basis for an improved good laboratory practice (GLP) for the commercial extraction and analysis of this multifunctional natural polymer.

G proteins coupled receptors (GPCRs) play essential developmental roles with functions in all of the immune, olfactory sensory systems amongst other systems as well as exhibiting essential roles in the central and peripheral nervous system. GPCRs are also major targets of pharmaceutical drugs currently used to treat a vast number of conditions. Despite their clear importance, the function of many GPCRs is still obscure. Identifying the physiological role of more GPCRs provides a niche for more drugs to be developed and thus more conditions to be treated. The C.elegans lat-1 gene encodes the latrophilin vertebrate homolog; it is a member of the adhesion GPCR family and is structurally related to the flamingo/CELSR, an essential component of planar cell polarity pathway. This study aims to phenotypically characterise lat-1 mutants in C.elegans to provide insights into the physiological role of this important member of adhesion GPCRs. lat-1 mutants exhibit several morphological defects throughout development and during vulva development. Analysing the embryonic development of such mutants also identified an anterior-posterior polarity defect. The results implicate a second evolutionary conserved subfamily of adhesion GPCRs in the control of tissue polarity and morphogenesis.

Comment les cellules établissent leurs formes et organisations internes est un problème biologique fondamental. Au cours de cette thèse, j’ai étudié le développement de la forme cellulaire et de la polarité chez la cellule de levure fissipare. Ces études sont fondées sur l’exploration de la façon dont les petites spores symétriques de levures se développent et s’organisent pour briser la symétrie pour la définition de leur tout premier axe de polarité. Dans une première partie, j’ai étudié les couplages entre la mécanique de surface de la paroi cellulaire des spores et la stabilité de domaines de polarité de Cdc42 qui contrôlent les aspects spatio-temporelles de la brisure de symétrie de ces spores. Dans une seconde partie, j’ai étudié les mécanismes par lesquels ces domaines de polarité contrôlent leur taille et l'adapte à la géométrie de la cellule, un processus vraisemblablement pertinents pour comprendre comment des domaines fonctionnels corticaux s’adaptent à la taille des cellules. Globalement, ces nouvelles recherches focalisant sur la façon dont les cellules développent dynamiquement leur forme et polarité de novo, permettent de mettre en évidence des couplages complexes dans la morphogenèse qui ne peuvent pas être testés en regardant les cellules à « l’état stationnaire» ou avec des outils génétiques. / How cells establish their proper shapes and organization is a fundamental biological problem. In this thesis, I investigated the dynamic development of cellular form and polarity in the rod-shape fission yeast cell. These studies are based on monitoring how small symmetric fission yeast spores grow and self-organize to break symmetry for the definition of their very first polarity axis. In a first part, I studied interplays between surface mechanics of the spore cell wall and the stability of Cdc42-based polarity domains which control spatio-temporal aspects of spore symmetry breaking. In a second part, I studied mechanisms by which these polarity domains control their width and adapt it to cell surface geometry, a process likely relevant to understand how functional cortical domains scale to cell size. Overall these novel investigations focusing on how cells dynamically develop their form and polarity de novo highlight complex feedbacks in morphogenesis that cannot be evidenced by looking at cells at “steady state” or with genetics.