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Morphogenesis one century after On Growth and Form [EDITORIAL]

2017-11-28T04:00:31-08:00

Thomas Lecuit and L. Mahadevan




On Growth and Form in context - an interview with Matthew Jarron [SPOTLIGHT]

2017-11-28T04:00:31-08:00

Aidan Maartens

D'Arcy Thompson was born in 1860, trained in Edinburgh and Cambridge, and held positions in Dundee and St Andrews, where he worked until his death in 1948. On Growth and Form, his classic work on the mathematical patterns and physical rules underlying biological forms, was first published in 1917. To learn more about the book's context, we met Matthew Jarron, Curator of Museum Services at the University of Dundee, in the University's D'Arcy Thompson Zoology Museum. Surrounded by specimens, many of which were collected by Thompson himself, we discussed the legacy of On Growth and Form and the life of the man behind it.




On genes and form [REVIEW]

2017-11-28T04:00:31-08:00

Enrico Coen, Richard Kennaway, and Christopher Whitewoods

The mechanisms by which organisms acquire their sizes and shapes through growth was a major focus of D'Arcy Thompson's book On Growth and Form. By applying mathematical and physical principles to a range of biological forms, Thompson achieved fresh insights, such as the notion that diverse biological shapes could be related through simple deformations of a coordinate system. However, Thompson considered genetics to lie outside the scope of his work, even though genetics was a growing discipline at the time the book was published. Here, we review how recent advances in cell, developmental, evolutionary and computational biology allow Thompson's ideas to be integrated with genes and the processes they influence to provide a deeper understanding of growth and morphogenesis. We consider how genes interact with subcellular-, cellular- and tissue-level processes in plants to yield patterns of growth that underlie the developmental and evolutionary shape transformations Thompson so eloquently described.




Computer modeling in developmental biology: growing today, essential tomorrow [REVIEW]

2017-11-28T04:00:31-08:00

James Sharpe

D'Arcy Thompson was a true pioneer, applying mathematical concepts and analyses to the question of morphogenesis over 100 years ago. The centenary of his famous book, On Growth and Form, is therefore a great occasion on which to review the types of computer modeling now being pursued to understand the development of organs and organisms. Here, I present some of the latest modeling projects in the field, covering a wide range of developmental biology concepts, from molecular patterning to tissue morphogenesis. Rather than classifying them according to scientific question, or scale of problem, I focus instead on the different ways that modeling contributes to the scientific process and discuss the likely future of modeling in developmental biology.




'The Forms of Tissues, or Cell-aggregates: D'Arcy Thompson's influence and its limits [REVIEW]

2017-11-28T04:00:31-08:00

Francois Graner and Daniel Riveline

In two chapters of his book On Growth and Form, D'Arcy Thompson used numerous biological and physical observations to show how principles from mathematics and physics – such as pressure differences, surface tension and viscosity – could explain cell shapes and packing within tissues. In this Review, we depict influences that enabled the genesis of his ideas, report examples of his visionary observations and trace his impact over the past 100 years. Recently, his ideas have been revisited as a new field of research emerged, linking cell-level physics with epithelial tissue structure and development. We critically discuss the potential and the limitations of both Thompson's and the modern approaches.




Mechanical control of growth: ideas, facts and challenges [REVIEW]

2017-11-28T04:00:31-08:00

Kenneth D. Irvine and Boris I. Shraiman

In his classic book On Growth and Form, D'Arcy Thompson discussed the necessity of a physical and mathematical approach to understanding the relationship between growth and form. The past century has seen extraordinary advances in our understanding of biological components and processes contributing to organismal morphogenesis, but the mathematical and physical principles involved have not received comparable attention. The most obvious entry of physics into morphogenesis is via tissue mechanics. In this Review, we discuss the fundamental role of mechanical interactions between cells induced by growth in shaping a tissue. Non-uniform growth can lead to accumulation of mechanical stress, which in the context of two-dimensional sheets of tissue can specify the shape it assumes in three dimensions. A special class of growth patterns – conformal growth – does not lead to the accumulation of stress and can generate a rich variety of planar tissue shapes. Conversely, mechanical stress can provide a regulatory feedback signal into the growth control circuit. Both theory and experiment support a key role for mechanical interactions in shaping tissues and, via mechanical feedback, controlling epithelial growth.




Tension, contraction and tissue morphogenesis [REVIEW]

2017-11-28T04:00:31-08:00

Natalie C. Heer and Adam C. Martin

D'Arcy Thompson was a proponent of applying mathematical and physical principles to biological systems, an approach that is becoming increasingly common in developmental biology. Indeed, the recent integration of quantitative experimental data, force measurements and mathematical modeling has changed our understanding of morphogenesis – the shaping of an organism during development. Emerging evidence suggests that the subcellular organization of contractile cytoskeletal networks plays a key role in force generation, while on the tissue level the spatial organization of forces determines the morphogenetic output. Inspired by D'Arcy Thompson's On Growth and Form, we review our current understanding of how biological forms are created and maintained by the generation and organization of contractile forces at the cell and tissue levels. We focus on recent advances in our understanding of how cells actively sculpt tissues and how forces are involved in specific morphogenetic processes.




Understanding the extracellular forces that determine cell fate and maintenance [REVIEW]

2017-11-28T04:00:31-08:00

Aditya Kumar, Jesse K. Placone, and Adam J. Engler

Stem cells interpret signals from their microenvironment while simultaneously modifying the niche through secreting factors and exerting mechanical forces. Many soluble stem cell cues have been determined over the past century, but in the past decade, our molecular understanding of mechanobiology has advanced to explain how passive and active forces induce similar signaling cascades that drive self-renewal, migration, differentiation or a combination of these outcomes. Improvements in stem cell culture methods, materials and biophysical tools that assess function have improved our understanding of these cascades. Here, we summarize these advances and offer perspective on ongoing challenges.




Mechanical regulation of musculoskeletal system development [REVIEW]

2017-11-28T04:00:31-08:00

Neta Felsenthal and Elazar Zelzer

During embryogenesis, the musculoskeletal system develops while containing within itself a force generator in the form of the musculature. This generator becomes functional relatively early in development, exerting an increasing mechanical load on neighboring tissues as development proceeds. A growing body of evidence indicates that such mechanical forces can be translated into signals that combine with the genetic program of organogenesis. This unique situation presents both a major challenge and an opportunity to the other tissues of the musculoskeletal system, namely bones, joints, tendons, ligaments and the tissues connecting them. Here, we summarize the involvement of muscle-induced mechanical forces in the development of various vertebrate musculoskeletal components and their integration into one functional unit.




The old and new faces of morphology: the legacy of D'Arcy Thompson's 'theory of transformations' and 'laws of growth' [REVIEW]

2017-11-28T04:00:31-08:00

Arhat Abzhanov

In 1917, the publication of On Growth and Form by D'Arcy Wentworth Thompson challenged both mathematicians and naturalists to think about biological shapes and diversity as more than a confusion of chaotic forms generated at random, but rather as geometric shapes that could be described by principles of physics and mathematics. Thompson's work was based on the ideas of Galileo and Goethe on morphology and of Russell on functionalism, but he was first to postulate that physical forces and internal growth parameters regulate biological forms and could be revealed via geometric transformations in morphological space. Such precise mathematical structure suggested a unifying generative process, as reflected in the title of the book. To Thompson it was growth that could explain the generation of any particular biological form, and changes in ontogeny, rather than natural selection, could then explain the diversity of biological shapes. Whereas adaptationism, widely accepted in evolutionary biology, gives primacy to extrinsic factors in producing morphological variation, Thompson's ‘laws of growth' provide intrinsic directives and constraints for the generation of individual shapes, helping to explain the ‘profusion of forms, colours, and other modifications' observed in the living world.




Anisotropic shear stress patterns predict the orientation of convergent tissue movements in the embryonic heart [RESEARCH REPORT]

2017-11-28T04:00:31-08:00

Francesco Boselli, Emily Steed, Jonathan B. Freund, and Julien Vermot

Myocardial contractility and blood flow provide essential mechanical cues for the morphogenesis of the heart. In general, endothelial cells change their migratory behavior in response to shear stress patterns, according to flow directionality. Here, we assessed the impact of shear stress patterns and flow directionality on the behavior of endocardial cells, the specialized endothelial cells of the heart. At the early stages of zebrafish heart valve formation, we show that endocardial cells are converging to the valve-forming area and that this behavior depends upon mechanical forces. Quantitative live imaging and mathematical modeling allow us to correlate this tissue convergence with the underlying flow forces. We predict that tissue convergence is associated with the direction of the mean wall shear stress and of the gradient of harmonic phase-averaged shear stresses, which surprisingly do not match the overall direction of the flow. This contrasts with the usual role of flow directionality in vascular development and suggests that the full spatial and temporal complexity of the wall shear stress should be taken into account when studying endothelial cell responses to flow in vivo.




Microfluidic chest cavities reveal that transmural pressure controls the rate of lung development [RESEARCH REPORT]

2017-11-28T04:00:31-08:00

Celeste M. Nelson, Jason P. Gleghorn, Mei-Fong Pang, Jacob M. Jaslove, Katharine Goodwin, Victor D. Varner, Erin Miller, Derek C. Radisky, and Howard A. Stone

Mechanical forces are increasingly recognized to regulate morphogenesis, but how this is accomplished in the context of the multiple tissue types present within a developing organ remains unclear. Here, we use bioengineered ‘microfluidic chest cavities’ to precisely control the mechanical environment of the fetal lung. We show that transmural pressure controls airway branching morphogenesis, the frequency of airway smooth muscle contraction, and the rate of developmental maturation of the lungs, as assessed by transcriptional analyses. Time-lapse imaging reveals that branching events are synchronized across distant locations within the lung, and are preceded by long-duration waves of airway smooth muscle contraction. Higher transmural pressure decreases the interval between systemic smooth muscle contractions and increases the rate of morphogenesis of the airway epithelium. These data reveal that the mechanical properties of the microenvironment instruct crosstalk between different tissues to control the development of the embryonic lung.




The apical ECM preserves embryonic integrity and distributes mechanical stress during morphogenesis [RESEARCH ARTICLE]

2017-11-28T04:00:31-08:00

Thanh Thi Kim Vuong-Brender, Shashi Kumar Suman, and Michel Labouesse

Epithelia are bound by both basal and apical extracellular matrices (ECM). Although the composition and function of the former have been intensively investigated, less is known about the latter. The embryonic sheath, the ECM apical to the Caenorhabditis elegans embryonic epidermis, has been suggested to promote elongation of the embryo. In an RNAi screen for the components of the sheath, we identified the zona pellucida domain proteins NOAH-1 and NOAH-2. We found that these proteins act in the same pathway, and in parallel to three other putative sheath proteins, the leucine-rich repeat proteins SYM-1, LET-4 and FBN-1/Fibrillin, to ensure embryonic integrity and promote elongation. Laser nano-ablation experiments to map the stress field show that NOAH-1 and NOAH-2, together with PAK-1/p21-activated kinase, maintain and relay the actomyosin-dependent stress generated within the lateral epidermis before muscles become active. Subsequently, loss-of-function experiments show that apical ECM proteins are essential for muscle anchoring and for relaying the mechanical input from muscle contractions, which are essential for elongation. Hence, the apical ECM contributes to morphogenesis by maintaining embryonic integrity and relaying mechanical stress.




Variations in basement membrane mechanics are linked to epithelial morphogenesis [RESEARCH ARTICLE]

2017-11-28T04:00:31-08:00

Julien Chlasta, Pascale Milani, Gaël Runel, Jean-Luc Duteyrat, Leticia Arias, Laurie-Anne Lamire, Arezki Boudaoud, and Muriel Grammont

The regulation of morphogenesis by the basement membrane (BM) may rely on changes in its mechanical properties. To test this, we developed an atomic force microscopy-based method to measure BM mechanical stiffness during two key processes in Drosophila ovarian follicle development. First, follicle elongation depends on epithelial cells that collectively migrate, secreting BM fibrils perpendicularly to the anteroposterior axis. Our data show that BM stiffness increases during this migration and that fibril incorporation enhances BM stiffness. In addition, stiffness heterogeneity, due to oriented fibrils, is important for egg elongation. Second, epithelial cells change their shape from cuboidal to either squamous or columnar. We prove that BM softens around the squamous cells and that this softening depends on the TGFβ pathway. We also demonstrate that interactions between BM constituents are necessary for cell flattening. Altogether, these results show that BM mechanical properties are modified during development and that, in turn, such mechanical modifications influence both cell and tissue shapes.




Mechanical and signaling roles for keratin intermediate filaments in the assembly and morphogenesis of Xenopus mesendoderm tissue at gastrulation [RESEARCH ARTICLE]

2017-11-28T04:00:31-08:00

Pooja R. Sonavane, Chong Wang, Bette Dzamba, Gregory F. Weber, Ammasi Periasamy, and Douglas W. DeSimone

The coordination of individual cell behaviors is a crucial step in the assembly and morphogenesis of tissues. Xenopus mesendoderm cells migrate collectively along a fibronectin (FN) substrate at gastrulation, but how the adhesive and mechanical forces required for these movements are generated and transmitted is unclear. Traction force microscopy (TFM) was used to establish that traction stresses are limited primarily to leading edge cells in mesendoderm explants, and that these forces are balanced by intercellular stresses in follower rows. This is further reflected in the morphology of these cells, with broad lamellipodial protrusions, mature focal adhesions and a gradient of activated Rac1 evident at the leading edge, while small protrusions, rapid turnover of immature focal adhesions and lack of a Rac1 activity gradient characterize cells in following rows. Depletion of keratin (krt8) with antisense morpholinos results in high traction stresses in follower row cells, misdirected protrusions and the formation of actin stress fibers anchored in streak-like focal adhesions. We propose that maintenance of mechanical integrity in the mesendoderm by keratin intermediate filaments is required to balance stresses within the tissue to regulate collective cell movements.




Branching morphogenesis in the developing kidney is governed by rules that pattern the ureteric tree [RESEARCH ARTICLE]

2017-11-28T04:00:31-08:00

James G. Lefevre, Kieran M. Short, Timothy O. Lamberton, Odysse Michos, Daniel Graf, Ian M. Smyth, and Nicholas A. Hamilton

Metanephric kidney development is orchestrated by the iterative branching morphogenesis of the ureteric bud. We describe an underlying patterning associated with the ramification of this structure and show that this pattern is conserved between developing kidneys, in different parts of the organ and across developmental time. This regularity is associated with a highly reproducible branching asymmetry that is consistent with locally operative growth mechanisms. We then develop a class of tip state models to represent elaboration of the ureteric tree and describe rules for ‘half-delay’ branching morphogenesis that describe almost perfectly the patterning of this structure. Spatial analysis suggests that the observed asymmetry may arise from mutual suppression of bifurcation, but not extension, between the growing ureteric tips, and demonstrates that disruption of patterning occurs in mouse mutants in which the distribution of tips on the surface of the kidney is altered. These findings demonstrate that kidney development occurs by way of a highly conserved reiterative pattern of asymmetric bifurcation that is governed by intrinsic and locally operative mechanisms.




Pavement cells and the topology puzzle [RESEARCH ARTICLE]

2017-11-28T04:00:31-08:00

Ross Carter, Yara E. Sanchez-Corrales, Matthew Hartley, Veronica A. Grieneisen, and Athanasius F. M. Maree

D'Arcy Thompson emphasised the importance of surface tension as a potential driving force in establishing cell shape and topology within tissues. Leaf epidermal pavement cells grow into jigsaw-piece shapes, highly deviating from such classical forms. We investigate the topology of developing Arabidopsis leaves composed solely of pavement cells. Image analysis of around 50,000 cells reveals a clear and unique topological signature, deviating from previously studied epidermal tissues. This topological distribution is established early during leaf development, already before the typical pavement cell shapes emerge, with topological homeostasis maintained throughout growth and unaltered between division and maturation zones. Simulating graph models, we identify a heuristic cellular division rule that reproduces the observed topology. Our parsimonious model predicts how and when cells effectively place their division plane with respect to their neighbours. We verify the predicted dynamics through in vivo tracking of 800 mitotic events, and conclude that the distinct topology is not a direct consequence of the jigsaw piece-like shape of the cells, but rather owes itself to a strongly life history-driven process, with limited impact from cell-surface mechanics.




Clones of cells switch from reduction to enhancement of size variability in Arabidopsis sepals [RESEARCH ARTICLE]

2017-11-28T04:00:31-08:00

Satoru Tsugawa, Nathan Hervieux, Daniel Kierzkowski, Anne-Lise Routier-Kierzkowska, Aleksandra Sapala, Olivier Hamant, Richard S. Smith, Adrienne H. K. Roeder, Arezki Boudaoud, and Chun-Biu Li

Organs form with remarkably consistent sizes and shapes during development, whereas a high variability in growth is observed at the cell level. Given this contrast, it is unclear how such consistency in organ scale can emerge from cellular behavior. Here, we examine an intermediate scale, the growth of clones of cells in Arabidopsis sepals. Each clone consists of the progeny of a single progenitor cell. At early stages, we find that clones derived from a small progenitor cell grow faster than those derived from a large progenitor cell. This results in a reduction in clone size variability, a phenomenon we refer to as size uniformization. By contrast, at later stages of clone growth, clones change their growth pattern to enhance size variability, when clones derived from larger progenitor cells grow faster than those derived from smaller progenitor cells. Finally, we find that, at early stages, fast growing clones exhibit greater cell growth heterogeneity. Thus, cellular variability in growth might contribute to a decrease in the variability of clones throughout the sepal.




Cell dynamics underlying oriented growth of the Drosophila wing imaginal disc [RESEARCH ARTICLE]

2017-11-28T04:00:31-08:00

Natalie A. Dye, Marko Popovic, Stephanie Spannl, Raphaël Etournay, Dagmar Kainmüller, Suhrid Ghosh, Eugene W. Myers, Frank Jülicher, and Suzanne Eaton

Quantitative analysis of the dynamic cellular mechanisms shaping the Drosophila wing during its larval growth phase has been limited, impeding our ability to understand how morphogen patterns regulate tissue shape. Such analysis requires explants to be imaged under conditions that maintain both growth and patterning, as well as methods to quantify how much cellular behaviors change tissue shape. Here, we demonstrate a key requirement for the steroid hormone 20-hydroxyecdysone (20E) in the maintenance of numerous patterning systems in vivo and in explant culture. We find that low concentrations of 20E support prolonged proliferation in explanted wing discs in the absence of insulin, incidentally providing novel insight into the hormonal regulation of imaginal growth. We use 20E-containing media to observe growth directly and to apply recently developed methods for quantitatively decomposing tissue shape changes into cellular contributions. We discover that whereas cell divisions drive tissue expansion along one axis, their contribution to expansion along the orthogonal axis is cancelled by cell rearrangements and cell shape changes. This finding raises the possibility that anisotropic mechanical constraints contribute to growth orientation in the wing disc.




Organ size control via hydraulically gated oscillations [RESEARCH ARTICLE]

2017-11-28T04:00:31-08:00

Teresa Ruiz-Herrero, Kevin Alessandri, Basile V. Gurchenkov, Pierre Nassoy, and L. Mahadevan

Hollow vesicular tissues of various sizes and shapes arise in biological organs such as ears, guts, hearts, brains and even entire organisms. Regulating their size and shape is crucial for their function. Although chemical signaling has been thought to play a role in the regulation of cellular processes that feed into larger scales, it is increasingly recognized that mechanical forces are involved in the modulation of size and shape at larger length scales. Motivated by a variety of examples of tissue cyst formation and size control that show simultaneous growth and size oscillations, we create a minimal theoretical framework for the growth and dynamics of a soft, fluid-permeable, spherical shell. We show that these shells can relieve internal pressure by bursting intermittently, shrinking and re-growing, providing a simple mechanism by which hydraulically gated oscillations can regulate size. To test our theory, we develop an in vitro experimental set-up to monitor the growth and oscillations of a hollow tissue spheroid growing freely or when confined. A simple generalization of our theory to account for irreversible deformations allows us to explain the time scales and the amplitudes of oscillations in terms of the geometry and mechanical properties of the tissue shells. Taken together, our theory and experimental observations show how soft hydraulics can regulate the size of growing tissue shells.




Phyllotactic regularity requires the Paf1 complex in Arabidopsis [RESEARCH ARTICLE]

2017-11-28T04:00:31-08:00

Kateryna Fal, Mengying Liu, Assem Duisembekova, Yassin Refahi, Elizabeth S. Haswell, and Olivier Hamant

In plants, aerial organs are initiated at stereotyped intervals, both spatially (every 137° in a pattern called phyllotaxis) and temporally (at prescribed time intervals called plastochrons). To investigate the molecular basis of such regularity, mutants with altered architecture have been isolated. However, most of them only exhibit plastochron defects and/or produce a new, albeit equally reproducible, phyllotactic pattern. This leaves open the question of a molecular control of phyllotaxis regularity. Here, we show that phyllotaxis regularity depends on the function of VIP proteins, components of the RNA polymerase II-associated factor 1 complex (Paf1c). Divergence angles between successive organs along the stem exhibited increased variance in vip3-1 and vip3-2 compared with the wild type, in two different growth conditions. Similar results were obtained with the weak vip3-6 allele and in vip6, a mutant for another Paf1c subunit. Mathematical analysis confirmed that these defects could not be explained solely by plastochron defects. Instead, increased variance in phyllotaxis in vip3 was observed at the meristem and related to defects in spatial patterns of auxin activity. Thus, the regularity of spatial, auxin-dependent, patterning at the meristem requires Paf1c.




An asymmetric attraction model for the diversity and robustness of cell arrangement in nematodes [RESEARCH ARTICLE]

2017-11-28T04:00:31-08:00

Kazunori Yamamoto and Akatsuki Kimura

During early embryogenesis in animals, cells are arranged into a species-specific pattern in a robust manner. Diverse cell arrangement patterns are observed, even among close relatives. In the present study, we evaluated the mechanisms by which the diversity and robustness of cell arrangements are achieved in developing embryos. We successfully reproduced various patterns of cell arrangements observed in various nematode species in Caenorhabditis elegans embryos by altering the eggshell shapes. The findings suggest that the observed diversity of cell arrangements can be explained by differences in the eggshell shape. Additionally, we found that the cell arrangement was robust against eggshell deformation. Computational modeling revealed that, in addition to repulsive forces, attractive forces are sufficient to achieve such robustness. The present model is also capable of simulating the effect of changing cell division orientation. Genetic perturbation experiments demonstrated that attractive forces derived from cell adhesion are necessary for the robustness. The proposed model accounts for both diversity and robustness of cell arrangements, and contributes to our understanding of how the diversity and robustness of cell arrangements are achieved in developing embryos.




A facilitated diffusion mechanism establishes the Drosophila Dorsal gradient [RESEARCH ARTICLE]

2017-11-28T04:00:31-08:00

Sophia N. Carrell, Michael D. O'Connell, Thomas Jacobsen, Amy E. Pomeroy, Stephanie M. Hayes, and Gregory T. Reeves

The transcription factor NF-B plays an important role in the immune system, apoptosis and inflammation. Dorsal, a Drosophila homolog of NF-B, patterns the dorsal-ventral axis in the blastoderm embryo. During this stage, Dorsal is sequestered outside the nucleus by the IB homolog Cactus. Toll signaling on the ventral side breaks the Dorsal/Cactus complex, allowing Dorsal to enter the nucleus to regulate target genes. Fluorescent data show that Dorsal accumulates on the ventral side of the syncytial blastoderm. Here, we use modeling and experimental studies to show that this accumulation is caused by facilitated diffusion, or shuttling, of the Dorsal/Cactus complex. We also show that active Toll receptors are limiting in wild-type embryos, which is a key factor in explaining global Dorsal gradient formation. Our results suggest that shuttling is necessary for viability of embryos from mothers with compromised dorsal levels. Therefore, Cactus not only has the primary role of regulating Dorsal nuclear import, but also has a secondary role in shuttling. Given that this mechanism has been found in other, independent, systems, we suggest that it might be more prevalent than previously thought.













Fibroblast growth factors: key players in regeneration and tissue repair [REVIEW]

2017-11-14T04:00:20-08:00

Luigi Maddaluno, Corinne Urwyler, and Sabine Werner

Tissue injury initiates a complex repair process, which in some organisms can lead to the complete regeneration of a tissue. In mammals, however, the repair of most organs is imperfect and results in scar formation. Both regeneration and repair are orchestrated by a highly coordinated interplay of different growth factors and cytokines. Among the key players are the fibroblast growth factors (FGFs), which control the migration, proliferation, differentiation and survival of different cell types. In addition, FGFs influence the expression of other factors involved in the regenerative response. Here, we summarize current knowledge on the roles of endogenous FGFs in regeneration and repair in different organisms and in different tissues and organs. Gaining a better understanding of these FGF activities is important for appropriate modulation of FGF signaling after injury to prevent impaired healing and to promote organ regeneration in humans.




The evolution of cortical development: the synapsid-diapsid divergence [REVIEW]

2017-11-14T04:00:20-08:00

Andre M. Goffinet

The cerebral cortex covers the rostral part of the brain and, in higher mammals and particularly humans, plays a key role in cognition and consciousness. It is populated with neuronal cell bodies distributed in radially organized layers. Understanding the common and lineage-specific molecular mechanisms that orchestrate cortical development and evolution are key issues in neurobiology. During evolution, the cortex appeared in stem amniotes and evolved divergently in two main branches of the phylogenetic tree: the synapsids (which led to present day mammals) and the diapsids (reptiles and birds). Comparative studies in organisms that belong to those two branches have identified some common principles of cortical development and organization that are possibly inherited from stem amniotes and regulated by similar molecular mechanisms. These comparisons have also highlighted certain essential features of mammalian cortices that are absent or different in diapsids and that probably evolved after the synapsid-diapsid divergence. Chief among these is the size and multi-laminar organization of the mammalian cortex, and the propensity to increase its area by folding. Here, I review recent data on cortical neurogenesis, neuronal migration and cortical layer formation and folding in this evolutionary perspective, and highlight important unanswered questions for future investigation.




Developing a sense of touch [REVIEW]

2017-11-14T04:00:20-08:00

Blair A. Jenkins and Ellen A. Lumpkin

The sensation of touch is mediated by mechanosensory neurons that are embedded in skin and relay signals from the periphery to the central nervous system. During embryogenesis, axons elongate from these neurons to make contact with the developing skin. Concurrently, the epithelium of skin transforms from a homogeneous tissue into a heterogeneous organ that is made up of distinct layers and microdomains. Throughout this process, each neuronal terminal must form connections with an appropriate skin region to serve its function. This Review presents current knowledge of the development of the sensory microdomains in mammalian skin and the mechanosensory neurons that innervate them.




The African Zika virus MR-766 is more virulent and causes more severe brain damage than current Asian lineage and dengue virus [RESEARCH ARTICLE]

2017-11-14T04:00:20-08:00

Qiang Shao, Stephanie Herrlinger, Ya-Nan Zhu, Mei Yang, Forrest Goodfellow, Steven L. Stice, Xiao-Peng Qi, Melinda A. Brindley, and Jian-Fu Chen

The Zika virus (ZIKV) has two lineages, Asian and African, and their impact on developing brains has not been compared. Dengue virus (DENV) is a close family member of ZIKV and co-circulates with ZIKV. Here, we performed intracerebral inoculation of embryonic mouse brains with dengue virus 2 (DENV2), and found that DENV2 is sufficient to cause smaller brain size due to increased cell death in neural progenitor cells (NPCs) and neurons. Compared with the currently circulating Asian lineage of ZIKV (MEX1-44), DENV2 grows slower, causes less neuronal death and fails to cause postnatal animal death. Surprisingly, our side-by-side comparison uncovered that the African ZIKV isolate (MR-766) is more potent at causing brain damage and postnatal lethality than MEX1-44. In comparison with MEX1-44, MR-766 grows faster in NPCs and in the developing brain, and causes more pronounced cell death in NPCs and neurons, resulting in more severe neuronal loss. Together, these results reveal that DENV2 is sufficient to cause smaller brain sizes, and suggest that the ZIKV African lineage is more toxic and causes more potent brain damage than the Asian lineage.




Synaptic input as a directional cue for migrating interneuron precursors [RESEARCH ARTICLE]

2017-11-14T04:00:20-08:00

Annika K. Wefers, Christian Haberlandt, Nuriye B. Tekin, Dmitry A. Fedorov, Aline Timmermann, Johannes J. L. van der Want, Farrukh A. Chaudhry, Christian Steinhäuser, Karl Schilling, and Ronald Jabs

During CNS development, interneuron precursors have to migrate extensively before they integrate in specific microcircuits. Known regulators of neuronal motility include classical neurotransmitters, yet the mechanisms that assure interneuron dispersal and interneuron/projection neuron matching during histogenesis remain largely elusive. We combined time-lapse video microscopy and electrophysiological analysis of the nascent cerebellum of transgenic Pax2-EGFP mice to address this issue. We found that cerebellar interneuronal precursors regularly show spontaneous postsynaptic currents, indicative of synaptic innervation, well before settling in the molecular layer. In keeping with the sensitivity of these cells to neurotransmitters, ablation of synaptic communication by blocking vesicular release in acute slices of developing cerebella slows migration. Significantly, abrogation of exocytosis primarily impedes the directional persistence of migratory interneuronal precursors. These results establish an unprecedented function of the early synaptic innervation of migrating neuronal precursors and demonstrate a role for synapses in the regulation of migration and pathfinding.




Regulation of mitosis-meiosis transition by the ubiquitin ligase {beta}-TrCP in male germ cells [RESEARCH ARTICLE]

2017-11-14T04:00:20-08:00

Tadashi Nakagawa, Teng Zhang, Ryo Kushi, Seiji Nakano, Takahiro Endo, Makiko Nakagawa, Noriko Yanagihara, David Zarkower, and Keiko Nakayama

The mitosis-meiosis transition is essential for spermatogenesis. Specific and timely downregulation of the transcription factor DMRT1, and consequent induction of Stra8 expression, is required for this process in mammals, but the molecular mechanism has remained unclear. Here, we show that β-TrCP, the substrate recognition component of an E3 ubiquitin ligase complex, targets DMRT1 for degradation and thereby controls the mitosis-meiosis transition in mouse male germ cells. Conditional inactivation of β-TrCP2 in male germ cells of β-TrCP1 knockout mice resulted in sterility due to a lack of mature sperm. The β-TrCP-deficient male germ cells did not enter meiosis, but instead underwent apoptosis. The induction of Stra8 expression was also attenuated in association with the accumulation of DMRT1 at the Stra8 promoter in β-TrCP-deficient testes. DMRT1 contains a consensus β-TrCP degron sequence that was found to bind β-TrCP. Overexpression of β-TrCP induced the ubiquitylation and degradation of DMRT1. Heterozygous deletion of Dmrt1 in β-TrCP-deficient spermatogonia increased meiotic cells with a concomitant reduction of apoptosis. Collectively, our data indicate that β-TrCP regulates the transition from mitosis to meiosis in male germ cells by targeting DMRT1 for degradation.




Talin regulates integrin {beta}1-dependent and -independent cell functions in ureteric bud development [RESEARCH ARTICLE]

2017-11-14T04:00:20-08:00

Sijo Mathew, Riya J. Palamuttam, Glenda Mernaugh, Harini Ramalingam, Zhenwei Lu, Ming-Zhi Zhang, Shuta Ishibe, David R. Critchley, Reinhard Fässler, Ambra Pozzi, Charles R. Sanders, Thomas J. Carroll, and Roy Zent

Kidney collecting system development requires integrin-dependent cell-extracellular matrix interactions. Integrins are heterodimeric transmembrane receptors consisting of α and β subunits; crucial integrins in the kidney collecting system express the β1 subunit. The β1 cytoplasmic tail has two NPxY motifs that mediate functions by binding to cytoplasmic signaling and scaffolding molecules. Talins, scaffolding proteins that bind to the membrane proximal NPxY motif, are proposed to activate integrins and to link them to the actin cytoskeleton. We have defined the role of talin binding to the β1 proximal NPxY motif in the developing kidney collecting system in mice that selectively express a Y-to-A mutation in this motif. The mice developed a hypoplastic dysplastic collecting system. Collecting duct cells expressing this mutation had moderate abnormalities in cell adhesion, migration, proliferation and growth factor-dependent signaling. In contrast, mice lacking talins in the developing ureteric bud developed kidney agenesis and collecting duct cells had severe cytoskeletal, adhesion and polarity defects. Thus, talins are essential for kidney collecting duct development through mechanisms that extend beyond those requiring binding to the β1 integrin subunit NPxY motif.




Graf regulates hematopoiesis through GEEC endocytosis of EGFR [RESEARCH ARTICLE]

2017-11-14T04:00:20-08:00

Sungdae Kim, Minyeop Nahm, Najin Kim, Yumi Kwon, Joohyung Kim, Sukwoo Choi, Eun Young Choi, Jiwon Shim, Cheolju Lee, and Seungbok Lee

GTPase regulator associated with focal adhesion kinase 1 (GRAF1) is an essential component of the GPI-enriched endocytic compartment (GEEC) endocytosis pathway. Mutations in the human GRAF1 gene are associated with acute myeloid leukemia, but its normal role in myeloid cell development remains unclear. We show that Graf, the Drosophila ortholog of GRAF1, is expressed and specifically localizes to GEEC endocytic membranes in macrophage-like plasmatocytes. We also find that loss of Graf impairs GEEC endocytosis, enhances EGFR signaling and induces a plasmatocyte overproliferation phenotype that requires the EGFR signaling cascade. Mechanistically, Graf-dependent GEEC endocytosis serves as a major route for EGFR internalization at high, but not low, doses of the predominant Drosophila EGFR ligand Spitz (Spi), and is indispensable for efficient EGFR degradation and signal attenuation. Finally, Graf interacts directly with EGFR in a receptor ubiquitylation-dependent manner, suggesting a mechanism by which Graf promotes GEEC endocytosis of EGFR at high Spi. Based on our findings, we propose a model in which Graf functions to downregulate EGFR signaling by facilitating Spi-induced receptor internalization through GEEC endocytosis, thereby restraining plasmatocyte proliferation.




Myc cooperates with {beta}-catenin to drive gene expression in nephron progenitor cells [RESEARCH ARTICLE]

2017-11-14T04:00:20-08:00

Xinchao Pan, Courtney M. Karner, and Thomas J. Carroll

For organs to achieve their proper size, the processes of stem cell renewal and differentiation must be tightly regulated. We previously showed that in the developing kidney, Wnt9b regulates distinct β-catenin-dependent transcriptional programs in the renewing and differentiating populations of the nephron progenitor cells. How β-catenin stimulated these two distinct programs was unclear. Here, we show that β-catenin cooperates with the transcription factor Myc to activate the progenitor renewal program. Although in multiple contexts Myc is a target of β-catenin, our characterization of a cell type-specific enhancer for the Wnt9b/β-catenin target gene Fam19a5 shows that Myc and β-catenin cooperate to activate gene expression controlled by this element. This appears to be a more general phenomenon as we find that Myc is required for the expression of every Wnt9b/β-catenin progenitor renewal target assessed as well as for proper nephron endowment in vivo. This study suggests that, within the developing kidney, tissue-specific β-catenin activity is regulated by cooperation with cell type-specific transcription factors. This finding not only provides insight into the regulation of β-catenin target genes in the developing kidney, but will also advance our understanding of progenitor cell renewal in other cell types/organ systems in which Myc and β-catenin are co-expressed.




PFKFB4 control of AKT signaling is essential for premigratory and migratory neural crest formation [RESEARCH ARTICLE]

2017-11-14T04:00:20-08:00

Ana Leonor Figueiredo, Frederique Maczkowiak, Caroline Borday, Patrick Pla, Meghane Sittewelle, Caterina Pegoraro, and Anne H. Monsoro-Burq

Neural crest (NC) specification comprises an early phase, initiating immature NC progenitors formation at neural plate stage, and a later phase at neural fold stage, resulting in a functional premigratory NC that is able to delaminate and migrate. We found that the NC gene regulatory network triggers upregulation of pfkfb4 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4) during this late specification phase. As shown in previous studies, PFKFB4 controls AKT signaling in gastrulas and glycolysis rate in adult cells. Here, we focus on PFKFB4 function in NC during and after neurulation, using time-controlled or hypomorph depletions in vivo. We find that PFKFB4 is essential both for specification of functional premigratory NC and for its migration. PFKFB4-depleted embryos fail to activate n-cadherin and late NC specifiers, and exhibit severe migration defects resulting in craniofacial defects. AKT signaling mediates PFKFB4 function in NC late specification, whereas both AKT signaling and glycolysis regulate migration. These findings highlight novel and essential roles of PFKFB4 activity in later stages of NC development that are wired into the NC gene regulatory network.













An interview with Christiane Nüsslein-Volhard [SPOTLIGHT]

2017-10-31T04:00:25-07:00

Katherine Brown

Christiane Nüsslein-Volhard is Director Emeritus at the Max Planck Institute for Developmental Biology in Tübingen, Germany. In 1995, she was awarded the Nobel Prize for Physiology and Medicine, along with Eric Wieschaus and Edward Lewis, for her work on the genetic control of embryogenesis using the fruit fly Drosophila melanogaster. In the 1990s, she transitioned her lab to working with zebrafish (Danio rerio), using similar forward genetic approaches to those that had proved so successful in Drosophila to uncover key regulators of vertebrate development. We met with Christiane at the recent International Society for Developmental Biology (ISDB) meeting in Singapore, to talk about her research, the impact of the Nobel Prize and the challenges of being a ‘woman in science’.




Transcriptional precision and accuracy in development: from measurements to models and mechanisms [REVIEW]

2017-10-31T04:00:25-07:00

Lital Bentovim, Timothy T. Harden, and Angela H. DePace

During development, genes are transcribed at specific times, locations and levels. In recent years, the emergence of quantitative tools has significantly advanced our ability to measure transcription with high spatiotemporal resolution in vivo. Here, we highlight recent studies that have used these tools to characterize transcription during development, and discuss the mechanisms that contribute to the precision and accuracy of the timing, location and level of transcription. We attempt to disentangle the discrepancies in how physicists and biologists use the term ‘precision' to facilitate interactions using a common language. We also highlight selected examples in which the coupling of mathematical modeling with experimental approaches has provided important mechanistic insights, and call for a more expansive use of mathematical modeling to exploit the wealth of quantitative data and advance our understanding of animal transcription.




Cortical interneuron development: a tale of time and space [REVIEW]

2017-10-31T04:00:25-07:00

Jia Sheng Hu, Daniel Vogt, Magnus Sandberg, and John L. Rubenstein

Cortical interneurons are a diverse group of neurons that project locally and are crucial for regulating information processing and flow throughout the cortex. Recent studies in mice have advanced our understanding of how these neurons are specified, migrate and mature. Here, we evaluate new findings that provide insights into the development of cortical interneurons and that shed light on when their fate is determined, on the influence that regional domains have on their development, and on the role that key transcription factors and other crucial regulatory genes play in these events. We focus on cortical interneurons that are derived from the medial ganglionic eminence, as most studies have examined this interneuron population. We also assess how these data inform our understanding of neuropsychiatric disease and discuss the potential role of cortical interneurons in cell-based therapies.




A tectorin-based matrix and planar cell polarity genes are required for normal collagen-fibril orientation in the developing tectorial membrane [RESEARCH ARTICLE]

2017-10-31T04:00:25-07:00

Richard J. Goodyear, Xiaowei Lu, Michael R. Deans, and Guy P. Richardson

The tectorial membrane is an extracellular structure of the cochlea. It develops on the surface of the auditory epithelium and contains collagen fibrils embedded in a tectorin-based matrix. The collagen fibrils are oriented radially with an apically directed slant – a feature considered crucial for hearing. To determine how this pattern is generated, collagen-fibril formation was examined in mice lacking a tectorin-based matrix, epithelial cilia or the planar cell polarity genes Vangl2 and Ptk7. In wild-type mice, collagen-fibril bundles appear within a tectorin-based matrix at E15.5 and, as fibril number rapidly increases, become co-aligned and correctly oriented. Epithelial width measurements and data from Kif3acKO mice suggest, respectively, that radial stretch and cilia play little, if any, role in determining normal collagen-fibril orientation; however, evidence from tectorin-knockout mice indicates that confinement is important. PRICKLE2 distribution reveals the planar cell polarity axis in the underlying epithelium is organised along the length of the cochlea and, in mice in which this polarity is disrupted, the apically directed collagen offset is no longer observed. These results highlight the importance of the tectorin-based matrix and epithelial signals for precise collagen organisation in the tectorial membrane.




Drosophila Atg16 promotes enteroendocrine cell differentiation via regulation of intestinal Slit/Robo signaling [RESEARCH ARTICLE]

2017-10-31T04:00:25-07:00

Peter Nagy, Zsuzsanna Szatmari, Gyöngyver O. Sandor, Monika Lippai, Krisztina Hegedus, and Gabor Juhasz

Genetic variations of Atg16l1, Slit2 and Rab19 predispose to the development of inflammatory bowel disease (IBD), but the relationship between these mutations is unclear. Here we show that in Drosophila guts lacking the WD40 domain of Atg16, pre-enteroendocrine (pre-EE) cells accumulate that fail to differentiate into properly functioning secretory EE cells. Mechanistically, loss of Atg16 or its binding partner Rab19 impairs Slit production, which normally inhibits EE cell generation by activating Robo signaling in stem cells. Importantly, loss of Atg16 or decreased Slit/Robo signaling triggers an intestinal inflammatory response. Surprisingly, analysis of Rab19 and domain-specific Atg16 mutants indicates that their stem cell niche regulatory function is independent of autophagy. Our study reveals how mutations in these different genes may contribute to IBD.




Neural-specific deletion of the focal adhesion adaptor protein paxillin slows migration speed and delays cortical layer formation [RESEARCH ARTICLE]

2017-10-31T04:00:25-07:00

Mamunur Rashid, Judson Belmont, David Carpenter, Christopher E. Turner, and Eric C. Olson

Paxillin and Hic-5 are homologous focal adhesion adaptor proteins that coordinate cytoskeletal rearrangements in response to integrin signaling, but their role(s) in cortical development are unknown. Here, we find that Hic-5-deficient mice are postnatal viable with normal cortical layering. Mice with a neural-specific deletion of paxillin are also postnatal viable, but show evidence of a cortical neuron migration delay that is evident pre- and perinatally, but is not detected at postnatal day 35 (P35). This phenotype is not modified by Hic-5 deficiency (double knockout). Specific deletion of paxillin in postmitotic neurons using Nex-Cre-mediated recombination as well as in utero electroporation of a Cre-expression construct identified a cell-autonomous requirement for paxillin in migrating neurons. Paxillin-deficient neurons have shorter leading processes that exhibited multiple swellings in comparison with control. Multiphoton imaging revealed that paxillin-deficient neurons migrate ~30% slower than control neurons. This phenotype is similar to that produced by deletion of focal adhesion kinase (FAK), a signaling partner of paxillin, and suggests that paxillin and FAK function cell-autonomously to control migrating neuron morphology and speed during cortical development.




Nuclear movement regulated by non-Smad Nodal signaling via JNK is associated with Smad signaling during zebrafish endoderm specification [RESEARCH ARTICLE]

2017-10-31T04:00:25-07:00

Shunya Hozumi, Shun Aoki, and Yutaka Kikuchi

Asymmetric nuclear positioning is observed during animal development, but its regulation and significance in cell differentiation remain poorly understood. Using zebrafish blastulae, we provide evidence that nuclear movement towards the yolk syncytial layer, which comprises extraembryonic tissue, occurs in the first cells fated to differentiate into the endoderm. Nodal signaling is essential for nuclear movement, whereas nuclear envelope proteins are involved in movement through microtubule formation. Positioning of the microtubule-organizing center, which is proposed to be crucial for nuclear movement, is regulated by Nodal signaling and nuclear envelope proteins. The non-Smad JNK signaling pathway, which is downstream of Nodal signaling, regulates nuclear movement independently of the Smad pathway, and this nuclear movement is associated with Smad signal transduction toward the nucleus. Our study provides insight into the function of nuclear movement in Smad signaling toward the nucleus, and could be applied to the control of TGFβ signaling.




Dysregulated PDGFR{alpha} signaling alters coronal suture morphogenesis and leads to craniosynostosis through endochondral ossification [RESEARCH ARTICLE]

2017-10-31T04:00:25-07:00

Fenglei He and Philippe Soriano

Craniosynostosis is a prevalent human birth defect characterized by premature fusion of calvarial bones. In this study, we show that tight regulation of endogenous PDGFRα activity is required for normal calvarium development in the mouse and that dysregulated PDGFRα activity causes craniosynostosis. Constitutive activation of PDGFRα leads to expansion of cartilage underlying the coronal sutures, which contribute to suture closure through endochondral ossification, in a process regulated in part by PI3K/AKT signaling. Our results thus identify a novel mechanism underlying calvarial development in craniosynostosis.




The Dlx5-FGF10 signaling cascade controls cranial neural crest and myoblast interaction during oropharyngeal patterning and development [RESEARCH ARTICLE]

2017-10-31T04:00:25-07:00

Hideki Sugii, Alexandre Grimaldi, Jingyuan Li, Carolina Parada, Thach Vu-Ho, Jifan Feng, Junjun Jing, Yuan Yuan, Yuxing Guo, Hidefumi Maeda, and Yang Chai

Craniofacial development depends on cell-cell interactions, coordinated cellular movement and differentiation under the control of regulatory gene networks, which include the distal-less (Dlx) gene family. However, the functional significance of Dlx5 in patterning the oropharyngeal region has remained unknown. Here, we show that loss of Dlx5 leads to a shortened soft palate and an absence of the levator veli palatini, palatopharyngeus and palatoglossus muscles that are derived from the 4th pharyngeal arch (PA); however, the tensor veli palatini, derived from the 1st PA, is unaffected. Dlx5-positive cranial neural crest (CNC) cells are in direct contact with myoblasts derived from the pharyngeal mesoderm, and Dlx5 disruption leads to altered proliferation and apoptosis of CNC and muscle progenitor cells. Moreover, the FGF10 pathway is downregulated in Dlx5–/– mice, and activation of FGF10 signaling rescues CNC cell proliferation and myogenic differentiation in these mutant mice. Collectively, our results indicate that Dlx5 plays crucial roles in the patterning of the oropharyngeal region and development of muscles derived from the 4th PA mesoderm in the soft palate, likely via interactions between CNC-derived and myogenic progenitor cells.