YAP dysregulation triggers hypertrophy by CCN2 secretion and TGFβ uptake in human pluripotent stem cell-derived cardiomyocytes.

Hypertrophy Cardiomyopathy (HCM) is the most prevalent hereditary cardiovascular disease - affecting >1:500 individuals. Advanced forms of HCM clinically present with hypercontractility, hypertrophy and fibrosis. Several single-point mutations in b-myosin heavy chain (MYH7) have been associated with HCM and increased contractility at the organ level.

Learning a conserved mechanism for early neuroectoderm morphogenesis.

Morphogenesis is the process whereby the body of an organism develops its target shape. The morphogen BMP is known to play a conserved role across bilaterian organisms in determining the dorsoventral (DV) axis. Yet, how BMP governs the spatio-temporal dynamics of cytoskeletal proteins driving morphogenetic flow remains an open question.

Learning a conserved mechanism for early neuroectoderm morphogenesis.

Morphogenesis is the process whereby the body of an organism develops its target shape. The morphogen BMP is known to play a conserved role across bilaterian organisms in determining the dorsoventral (DV) axis. Yet, how BMP governs the spatio-temporal dynamics of cytoskeletal proteins driving morphogenetic flow remains an open question.

Active cell divisions generate fourfold orientationally ordered phase in living tissue.

Morphogenesis, the process through which genes generate form, establishes tissue-scale order as a template for constructing the complex shapes of the body plan. The extensive growth required to build these ordered substrates is fuelled by cell proliferation, which, naively, should destroy order. Understanding how active morphogenetic mechanisms couple cellular and mechanical processes to generate order-rather than annihilate it-remains an outstanding question in animal development.

Maintaining symmetry during body axis elongation.

Bilateral symmetry defines much of the animal kingdom and is crucial for numerous functions of bilaterian organisms. Genetic approaches have discovered highly conserved patterning networks that establish bilateral symmetry in early embryos, but how this symmetry is maintained throughout subsequent morphogenetic events remains largely unknown. Here we show that the terminal patterning system-which relies on Ras/ERK signaling through activation of the Torso receptor by its ligand Trunk-is critical for preserving bilateral symmetry during Drosophila body axis elongation, a process driven by cell rearrangements in the two identical lateral regions of the embryo and specified by the dorsal-ventral and anterior-posterior patterning systems.

Septins regulate border cell surface geometry, shape, and motility downstream of Rho in Drosophila.

Septins self-assemble into polymers that bind and deform membranes in vitro and regulate diverse cell behaviors in vivo. How their in vitro properties relate to their in vivo functions is under active investigation. Here, we uncover requirements for septins in detachment and motility of border cell clusters in the Drosophila ovary.

Geometric control of myosin II orientation during axis elongation.

The actomyosin cytoskeleton is a crucial driver of morphogenesis. Yet how the behavior of large-scale cytoskeletal patterns in deforming tissues emerges from the interplay of geometry, genetics, and mechanics remains incompletely understood. Convergent extension in embryos provides the opportunity to establish a quantitative understanding of the dynamics of anisotropic non-muscle myosin II.

Patterned mechanical feedback establishes a global myosin gradient.

Morphogenesis, the coordinated execution of developmental programs that shape embryos, raises many fundamental questions at the interface between physics and biology. In particular, how the dynamics of active cytoskeletal processes are coordinated across the surface of entire embryos to generate global cell flows is poorly understood. Two distinct regulatory principles have been identified: genetic programs and dynamic response to mechanical stimuli.

Visceral organ morphogenesis via calcium-patterned muscle constrictions.

Organ architecture is often composed of multiple laminar tissues arranged in concentric layers. During morphogenesis, the initial geometry of visceral organs undergoes a sequence of folding, adopting a complex shape that is vital for function. Genetic signals are known to impact form, yet the dynamic and mechanical interplay of tissue layers giving rise to organs' complex shapes remains elusive.

Human neural tube morphogenesis in vitro by geometric constraints.

Understanding human organ formation is a scientific challenge with far-reaching medical implications. Three-dimensional stem-cell cultures have provided insights into human cell differentiation. However, current approaches use scaffold-free stem-cell aggregates, which develop non-reproducible tissue shapes and variable cell-fate patterns.

Tissue topography steers migrating border cells.

Moving cells can sense and respond to physical features of the microenvironment; however, in vivo, the significance of tissue topography is mostly unknown. Here, we used border cells, an established model for in vivo cell migration, to study how chemical and physical information influences path selection. Although chemical cues were thought to be sufficient, live imaging, genetics, modeling, and simulations show that microtopography is also important.

Dynamic morphoskeletons in development.

Morphogenetic flows in developmental biology are characterized by the coordinated motion of thousands of cells that organize into tissues, naturally raising the question of how this collective organization arises. Using only the kinematics of tissue deformation, which naturally integrates local and global mechanisms along cell paths, we identify the dynamic morphoskeletons behind morphogenesis, i.e.

Topological structure and dynamics of three-dimensional active nematics.

Topological structures are effective descriptors of the nonequilibrium dynamics of diverse many-body systems. For example, motile, point-like topological defects capture the salient features of two-dimensional active liquid crystals composed of energy-consuming anisotropic units. We dispersed force-generating microtubule bundles in a passive colloidal liquid crystal to form a three-dimensional active nematic.

A variational method for image-based inference of internal stress in epithelial tissues.

Cellular mechanics drives epithelial morphogenesis, the process wherein cells collectively rearrange to produce tissue-scale deformations that determine organismal shape. However, quantitative understanding of tissue mechanics is impaired by the difficulty of direct measurement of stress . This difficulty has spurred the development of image-based inference algorithms that estimate stress from snapshots of epithelial geometry.

Extracellular matrix stiffness cues junctional remodeling for 3D tissue elongation.

Organs are sculpted by extracellular as well as cell-intrinsic forces, but how collective cell dynamics are orchestrated in response to environmental cues is poorly understood. Here we apply advanced image analysis to reveal extracellular matrix-responsive cell behaviors that drive elongation of the Drosophila follicle, a model system in which basement membrane stiffness instructs three-dimensional tissue morphogenesis. Through in toto morphometric analyses of wild type and round egg mutants, we find that neither changes in average cell shape nor oriented cell division are required for appropriate organ shape.

EGFR signaling coordinates patterning with cell survival during Drosophila epidermal development.

Extensive apoptosis is often seen in patterning mutants, suggesting that tissues can detect and eliminate potentially harmful mis-specified cells. Here, we show that the pattern of apoptosis in the embryonic epidermis of Drosophila is not a response to fate mis-specification but can instead be explained by the limiting availability of prosurvival signaling molecules released from locations determined by patterning information. In wild-type embryos, the segmentation cascade elicits the segmental production of several epidermal growth factor receptor (EGFR) ligands, including the transforming growth factor Spitz (TGFα), and the neuregulin, Vein.

Global morphogenetic flow is accurately predicted by the spatial distribution of myosin motors.

During embryogenesis tissue layers undergo morphogenetic flow rearranging and folding into specific shapes. While developmental biology has identified key genes and local cellular processes, global coordination of tissue remodeling at the organ scale remains unclear. Here, we combine light-sheet microscopy of the embryo with quantitative analysis and physical modeling to relate cellular flow with the patterns of force generation during the gastrulation process.

Identification of a neural crest stem cell niche by Spatial Genomic Analysis.

The neural crest is an embryonic population of multipotent stem cells that form numerous defining features of vertebrates. Due to lack of reliable techniques to perform transcriptional profiling in intact tissues, it remains controversial whether the neural crest is a heterogeneous or homogeneous population. By coupling multiplex single molecule fluorescence in situ hybridization with machine learning algorithm based cell segmentation, we examine expression of 35 genes at single cell  resolution in vivo.

Symmetry Breaking in an Edgeless Epithelium by Fat2-Regulated Microtubule Polarity.

Planar cell polarity (PCP) information is a critical determinant of organ morphogenesis. While PCP in bounded epithelial sheets is increasingly well understood, how PCP is organized in tubular and acinar tissues is not. Drosophila egg chambers (follicles) are an acinus-like "edgeless epithelium" and exhibit a continuous, circumferential PCP that does not depend on pathways active in bounded epithelia; this follicle PCP directs formation of an ellipsoid rather than a spherical egg.

Tissue cartography: compressing bio-image data by dimensional reduction.

The high volumes of data produced by state-of-the-art optical microscopes encumber research. We developed a method that reduces data size and processing time by orders of magnitude while disentangling signal by taking advantage of the laminar structure of many biological specimens. Our Image Surface Analysis Environment automatically constructs an atlas of 2D images for arbitrarily shaped, dynamic and possibly multilayered surfaces of interest.

Spatial constraints control cell proliferation in tissues.

Control of cell proliferation is a fundamental aspect of tissue formation in development and regeneration. Cells experience various spatial and mechanical constraints depending on their environmental context in the body, but we do not fully understand if and how such constraints influence cell cycle progression and thereby proliferation patterns in tissues. Here, we study the impact of mechanical manipulations on the cell cycle of individual cells within a mammalian model epithelium.

Quantitative cell polarity imaging defines leader-to-follower transitions during collective migration and the key role of microtubule-dependent adherens junction formation.

The directed migration of cell collectives drives the formation of complex organ systems. A characteristic feature of many migrating collectives is a 'tissue-scale' polarity, whereby 'leader' cells at the edge of the tissue guide trailing 'followers' that become assembled into polarised epithelial tissues en route. Here, we combine quantitative imaging and perturbation approaches to investigate epithelial cell state transitions during collective migration and organogenesis, using the zebrafish lateral line primordium as an in vivo model.

Tubular endocytosis drives remodelling of the apical surface during epithelial morphogenesis in Drosophila.

During morphogenesis, remodelling of cell shape requires the expansion or contraction of plasma membrane domains. Here we identify a mechanism underlying the restructuring of the apical surface during epithelial morphogenesis in Drosophila. We show that the retraction of villous protrusions and subsequent apical plasma membrane flattening is an endocytosis-driven morphogenetic process.

Multiview light-sheet microscope for rapid in toto imaging.

We present a multiview selective-plane illumination microscope (MuVi-SPIM), comprising two detection and illumination objective lenses, that allows rapid in toto fluorescence imaging of biological specimens with subcellular resolution. The fixed geometrical arrangement of the imaging branches enables multiview data fusion in real time. The high speed of MuVi-SPIM allows faithful tracking of nuclei and cell shape changes, which we demonstrate through in toto imaging of the embryonic development of Drosophila melanogaster.