The villi of the human and chick gut are formed in similar step-wise progressions, wherein the mesenchyme and attached epithelium first fold into longitudinal ridges, then a zigzag pattern, and finally individual villi. We find that these steps of villification depend upon the sequential differentiation of the distinct smooth muscle layers of the gut, which restrict the expansion of the growing endoderm and mesenchyme, generating compressive stresses that lead to their buckling and folding. A quantitative computational model, incorporating measured properties of the developing gut, recapitulates the morphological patterns seen during villification in a variety of species. These results provide a mechanistic understanding of the formation of these elaborations of the lining of the gut, essential for providing sufficient surface area for nutrient absorption.

Primary cilia are microtubule-based organelles involved in signal transduction and project from the surface of most vertebrate cells. Proteins that can localize to the cilium, for example, Inversin and Bardet-Biedl syndrome (BBS) proteins, are implicated in both beta-catenin-dependent and -independent Wnt signalling. Given that Inversin and BBS proteins are found both at the cilium and elsewhere in the cell, the role of the cilium itself in Wnt signalling is not clear. Using three separate mutations that disrupt ciliogenesis (affecting Kif3a, Ift88 and Ofd1), we show in this study that the primary cilium restricts the activity of the canonical Wnt pathway in mouse embryos, primary fibroblasts, and embryonic stem cells. Interestingly, unciliated cells activate transcription only in response to Wnt stimulation, but do so much more robustly than ciliated cells. Loss of Kif3a, but not other ciliogenic genes, causes constitutive phosphorylation of Dishevelled (Dvl). Blocking the activity of casein kinase I (CKI) reverses this constitutive Dvl phosphorylation and abrogates pathway hyper-responsiveness. These results suggest that Kif3a restrains canonical Wnt signalling both by restricting the CKI-dependent phosphorylation of Dvl and through a separate ciliary mechanism. More generally, these findings reveal that, in contrast to its role in promoting Hedgehog (Hh) signalling, the cilium restrains canonical Wnt signalling.

Summary The developing vertebrate gut tube forms a reproducible looped pattern as it grows into the body cavity. Here we use developmental experiments to eliminate alternative models and show that gut looping morphogenesis is driven by the homogeneous and isotropic forces that arise from the relative growth between the gut tube and the anchoring dorsal mesenteric sheet, tissues that grow at different rates. A simple physical mimic, using a differentially strained composite of a pliable rubber tube and a soft latex sheet is consistent with this mechanism and produces similar patterns. We devise a mathematical theory and a computational model for the number, size and shape of intestinal loops based solely on the measurable geometry, elasticity and relative growth of the tissues. The predictions of our theory are quantitatively consistent with observations of intestinal loops at different stages of development in the chick embryo. Our model also accounts for the qualitative and quantitative variation in the distinct gut looping patterns seen in a variety of species including the quail, finch and mouse illuminating how the simple macroscopic mechanics of differential growth drives the morphology of the developing gut.

SUMMARY We address the mechanism by which adult intestinal stem cells (ISCs) become localized to base of each villus during embryonic development. We find that, early in gut development, proliferating progenitors expressing ISC markers are evenly distributed throughout the epithelium, in both the chick and mouse. However as the villi form, the putative stem cells become restricted to the base of the villi. This shift in the localization is driven by mechanically influenced reciprocal signaling between the epithelium and underlying mesenchyme. Buckling forces physically distort the shape of the morphogenic field causing local maxima of epithelial signals, in particular Shh, at the tip of each villus. This induces a suite of high threshold response genes in the underlying mesenchyme to form a signaling center called the “villus cluster.” Villus cluster signals, notably Bmp4, feed back on the overlying epithelium, to ultimately restrict the stem cells to the base of each villus.

The spacing of hair in mammals and feathers in birds is one of the most apparent morphological features of the skin. This pattern arises when uniform fields of progenitor cells diversify their molecular fate while adopting higher order structure. Using the nascent skin of the developing chicken embryo as a model system, we find that morphological and molecular symmetries are simultaneously broken by an emergent process of cellular self-organization. The key initiators of heterogeneity are dermal progenitors, which spontaneously aggregate through contractility-driven cellular pulling. Concurrently, this dermal cell aggregation triggers the mechanosensitive activation of β-catenin in adjacent epidermal cells, initiating the follicle gene expression program. Taken together, this mechanism provides a means of integrating mechanical and molecular perspectives of organ formation

Unlike other monoamine neurotransmitters, the mechanism by which the brain's histamine content is regulated remains unclear. In mammals, vesicular monoamine transporters (VMATs) are expressed exclusively in neurons and mediate the storage of histamine and other monoamines. We have studied the visual system of Drosophila melanogaster in which histamine is the primary neurotransmitter released from photoreceptor cells. We report here that a novel mRNA splice variant of Drosophila VMAT (DVMAT-B) is expressed not in neurons but rather in a small subset of glia in the lamina of the fly's optic lobe. Histamine contents are reduced by mutation of dVMAT, but can be partially restored by specifically expressing DVMAT-B in glia. Our results suggest a novel role for a monoamine transporter in glia that may be relevant to histamine homeostasis in other systems.

No abstract

p3 2. Dynamics of signalling in self-organized stem cell assemblies: Idse Heemskerk, Aryeh Warmflash -p4 3. Interplay between tissue growth, morphogen signalling, and pattern formation in development: Laura Bocanegra-Moreno, Kasumi Kishi, Anna Kicheva -p7 4. The biophysical basis of robust plant morphogenesis: Yuchen Long, Antoine Fruleux, Arezki Boudaoud -p11 5. Dynamics of morphogen gradient formation and signalling during development: Timothy E. Saunders -p14 6. Coupling morphogenesis and patterning during amniote gastrulation: Paolo Caldarelli, Arthur Michaut, Jerome Gros -p18 7. Supra-cellular actin fiber arrays and their role in animal morphogenesis: Yonit Maroudas-Sacks, Kinneret Keren -p22 8. Mechano-chemical models for morphogenesis and collective cell migration: Edouard Hannezo -p26 9. Guiding the formation of tissue structure through self-organization: Zev J Gartner -p30 10. Phase transitions, spatial control of mRNA localization and gene expression in syncytial fungi: Benjamin Stormo and Amy Gladfelter -p33 11. The role of mechanics in a "post-molecular" conception of morphogenesis: Alan Rodrigues, Amy Shyer -p37 12. Dynamic interplay between cell shape and division positioning in the morphogenesis of early embryos: Nicolas Minc -p41 13. Building a mechanical atlas of the preimplantation embryo: Jean-Léon Maître -p44 14. Physical principles of organization of the cell cycle and morphogenesis in early Drosophila embryos: Stefano Di Talia -p48 15. Dynamic interplay of cell contact geometry and signalling: Bassma Khamaisi, David Sprinzak -p51 16. From locally generated forces to global shape and back: Sham Tlili, Pierre-François Lenne -p55