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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.

The villi of the human and chick gut are formed in similar stepwise progressions, wherein the mesenchyme and attached epithelium first fold into longitudinal ridges, then a zigzag pattern, and lastly individual villi. We find that these steps of vilification depend on the sequential differentiation of the distinct smooth muscle layers of the girt, 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.

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 quail, finch and mouse, illuminating how the simple macroscopic mechanics of differential growth drives the morphology of the developing gut. The gut is twisted logically The human intestine, much longer overall than the human body, is tightly looped within the body cavity in a pattern that is very similar between individuals, and characteristic of species. A study of gut morphogenesis in the chick, combining cellular and developmental biology, biophysics and mathematical modelling, shows that the looping complex shape of the vertebrate gut is a simple consequence of mechanics. As a body grows, the gut inside grows faster. It is anchored at each end and suspended by a muscular sheet called the mesentery, so is forced into loops. The looping pattern is determined solely by the elasticity, geometry and relative rates of growth of mesentery and gut, but the various twists and turns and loops are very reproducible, occurring with the same number in the same location from individual to individual.

Primary cilia are microtubule-based organelles involved in signal transduction and project from the surface of most vertebrate cells 1 . Proteins that can localize to the cilium, for example, Inversin and Bardet-Biedl syndrome (BBS) proteins, are implicated in both β -catenin-dependent and -independent Wnt signalling 2 , 3 , 4 . 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 ) 5 , 6 , 7 , 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.

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.

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.

The vertebrate small intestine is responsible for nutrient absorption during digestion. To this end, the surface area of the gut tube is maximally expanded, both through a series of loops extending its length and via the development of a complex luminal topography. Here, I first examine the mechanism behind the formation of intestinal loops. I demonstrate that looping morphogenesis is driven by mechanical forces that arise from differential growth between the gut tube and the anchoring dorsal mesenteric sheet. A computational model based on measured parameters not only quantitatively predicts the looping pattern in chick, verifying that these physical forces are sufficient to explain the process, but also accounts for the variation in the gut looping patterns seen in other species. Second, I explore the formation of intestinal villi in chick. I find that intestinal villi form in a stepwise process as a result of physical forces generated as proliferating endodermal and mesenchymal tissues are constrained by sequentially differentiating layers of smooth muscle. A computational model incorporating measured differential growth and the geometric and physical properties of the developing chick gut recapitulates the morphological patterns seen during chick villi formation. I also demonstrate that the same basic biophysical processes underlie the formation of intestinal folds in frog and villi in mice. Finally, I focus on the process by which intestinal stem cells are ultimately localized to the base of each villus. The endoderm expresses the morphogen, Sonic hedgehog (Shh). As the luminal surface of the gut is deformed during villus formation there are resulting local maxima of Shh signaling in the mesenchyme. This results, at high threshold, in the induction of a new signaling center under the villus tip termed the villus cluster. This, in turn, feeds back to restrict proliferating progenitors in the endoderm, the presumptive precursors of the stem cells, to the base of each villus. Together, these studies provide new insight into the formation of the small intestine as a functional organ and highlight the interplay between physical forces, tissue-level growth, and signaling during development.

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.

The molecular characterization of tissue organization through spatial omics brings renewed attention to the issue, formulated in Wolpert’s French Flag, of how spatial patterns of cell state emerge. Here, we address the skeletal pattern of adjacent cartilage and soft tissue. We find that cellular and supracellular structures are co-constitutive and result in cell-ECM and cell-cell-based structures that canalize cartilage and soft tissue fate, respectively. A bistability in these fate-setting structures establishes pattern length scale and is sufficient to break symmetry in the mesenchyme. However, an adjacent epithelium, through signals like Wnt, can locally seed the bistability to ensure the epithelial-adjacency of soft tissue. Rather than acting in a graded manner to provide positional information, Wnt affects cell fate by promoting a supracellular structure. Together, these results support a solution to the French Flag problem where fate pattern originates through structural relations between cell and supracellular levels.