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The Turing, or reaction-diffusion (RD), model is one of the best-known theoretical models used to explain self-regulated pattern formation in the developing animal embryo. Although its real-world relevance was long debated, a number of compelling examples have gradually alleviated much of the skepticism surrounding the model. The RD model can generate a wide variety of spatial patterns, and mathematical studies have revealed the kinds of interactions required for each, giving this model the potential for application as an experimental working hypothesis in a wide variety of morphological phenomena. In this review, we describe the essence of this theory for experimental biologists unfamiliar with the model, using examples from experimental studies in which the RD model is effectively incorporated.

Myosin-II in epithelial morphogenesis Myosin-II has a central role in generating the forces that drive cell shape changes during embryo development. Thomas Lecuit and colleagues study germ-band extension in Drosophila , in which epithelial cells undergo an ordered process of intercalation resulting in tissue extension through remodelling of cell junctions. They find that cell-junction shrinkage is driven by polarized flow of medial myosin-II pulses towards junctions, which organizes the whole process of intercalation. In addition, the flow of myosin-II is driven by the polarized distribution of E-cadherin/β-catenin/ α-catenin complexes at adherens junctions. Thus, epithelial morphogenesis is driven by polarized contractile actomyosin flows emerging from interactions between E-cadherin and actomyosin networks. Here, germ-band extension in Drosophila is studied in which epithelial cells undergo an ordered process of intercalation resulting in tissue extension through remodelling of cell junctions. Cell junction shrinkage is driven by polarized flow of medial Myosin-II pulses towards junctions which organizes the whole process of intercalation. The flow of Myosin II is driven by the polarized distribution of E-cadherin complexes at adherens junctions. Thus, epithelial morphogenesis is driven by polarized contractile actomyosin flows emerging from interactions between E-cadherin and actomyosin networks. Force generation by Myosin-II motors on actin filaments drives cell and tissue morphogenesis 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 . In epithelia, contractile forces are resisted at apical junctions by adhesive forces dependent on E-cadherin 16 , which also transmits tension 6 , 17 , 18 , 19 . During Drosophila embryonic germband extension, tissue elongation is driven by cell intercalation 20 , which requires an irreversible and planar polarized remodelling of epithelial cell junctions 4 , 5 . We investigate how cell deformations emerge from the interplay between force generation and cortical force transmission during this remodelling in Drosophila melanogaster . The shrinkage of dorsal–ventral-oriented (‘vertical’) junctions during this process is known to require planar polarized junctional contractility by Myosin II (refs 4 , 5 , 7 , 12 ). Here we show that this shrinkage is not produced by junctional Myosin II itself, but by the polarized flow of medial actomyosin pulses towards ‘vertical’ junctions. This anisotropic flow is oriented by the planar polarized distribution of E-cadherin complexes, in that medial Myosin II flows towards ‘vertical’ junctions, which have relatively less E-cadherin than transverse junctions. Our evidence suggests that the medial flow pattern reflects equilibrium properties of force transmission and coupling to E-cadherin by α-Catenin. Thus, epithelial morphogenesis is not properly reflected by Myosin II steady state distribution but by polarized contractile actomyosin flows that emerge from interactions between E-cadherin and actomyosin networks.

Key Points A neuron can rapidly combine and transform the information it receives through its synaptic inputs before the information is converted into neuronal output. This transformation can be defined by the neuronal input–output (I–O) relationship. Changes in the I–O relationship can correspond to distinct arithmetic operations. During sustained rate-coded signalling, the neuron operates as a signal integrator (over a given time-window) and the neuronal I–O relationship is defined as the dependence of sustained output firing rate on the input rate. During sparse temporally correlated signalling, the neuron acts as a coincidence detector and the I–O relationship can be defined in terms of the dependence of spike probability on the number of coincident inputs or their temporal correlation. Additive and subtractive operations performed on driving inputs by distinct modulatory synaptic input correspond to shifts in the I–O relationship, without a change of shape. Multiplicative and divisive operations correspond to increases or decreases in the slope, or gain, of the I–O relationship. Both of these operations have been observed in vivo during different tasks. Additive operations are essential for linearly combining signals and for controlling the number of inputs required for signalling. In the temporal domain, additive operations control the width of the temporal correlation window that the neuron can respond to and thus the temporal properties of signals that can propagate through the network. Multiplicative operations, or gain changes, are important for signal amplification, normalization and preventing saturation of firing, thereby allowing efficient information transmission. Gain changes are essential for coordinate transforms and have been proposed to control the functional connectivity of networks. In the temporal domain, neural gain also controls the 'roll-off' of the temporal correlation window for synaptic integration. Both morphologically simple neurons and those with extensive dendritic trees possess a number of biophysical mechanisms, including inhibition, short-term synaptic plasticity, synaptic noise and somatic and dendritic conductances that enable them to perform additive and multiplicative operations on their synaptic inputs. Some biophysical mechanisms, such as voltage noise, are general in that they perform the same arithmetic operation (multiplication) on sustained rate-coded and sparse temporally coded signals. However, others seem to be tuned for either sustained rate-coding or sparse coding regimes. Widespread presynaptic and dendritic mechanisms enable spatially segregated inputs to be multiplied together, although other local dendritic conductances seem to be tuned to detect spatio-temporally correlated input onto a specific dendritic branch. An extensive tool kit of nonlinear mechanisms confers considerable computational power on individual neurons, enabling them to perform a range of arithmetic operations on signals encoded in a variety of different ways. Individual neurons transform the relationship between synaptic input and output firing by utilizing both linear and nonlinear mechanisms. Angus Silver discusses the various underlying biophysical mechanisms in relation to the complexity of neuronal morphology and the neural coding regimes in which they are likely to operate. The vast computational power of the brain has traditionally been viewed as arising from the complex connectivity of neural networks, in which an individual neuron acts as a simple linear summation and thresholding device. However, recent studies show that individual neurons utilize a wealth of nonlinear mechanisms to transform synaptic input into output firing. These mechanisms can arise from synaptic plasticity, synaptic noise, and somatic and dendritic conductances. This tool kit of nonlinear mechanisms confers considerable computational power on both morphologically simple and more complex neurons, enabling them to perform a range of arithmetic operations on signals encoded in a variety of different ways.

Key Points Resilient individuals demonstrate adaptive psychological and physiological stress responses to acute stress, trauma or more chronic forms of adversity. Resilience is an active process, not simply the absence of changes induced by stress. Examining stress responses at multiple phenotypic levels can help to delineate an integrative model of resilience. Positive emotions and cognitive reappraisal promote adaptive coping strategies and resilience. Complex interactions between an individual's genetic make-up and their history of exposure to environmental stressors influence the adaptability of stress response systems and neural circuitry function. Progress is being made in identifying the neural circuits in the brain that mediate resilience. Recent work has begun to identify specific changes in gene expression and chromatin remodelling (that is, epigenetic adaptations) that underlie resilience. Although stress is associated with many physical and mental illnesses, most individuals cope well with it. Feder and colleagues review the factors that underlie stress resilience, showing that it involves adaptive changes in specific neural circuits, neuromodulator levels and molecular pathways. Every individual experiences stressful life events. In some cases acute or chronic stress leads to depression and other psychiatric disorders, but most people are resilient to such effects. Recent research has begun to identify the environmental, genetic, epigenetic and neural mechanisms that underlie resilience, and has shown that resilience is mediated by adaptive changes in several neural circuits involving numerous neurotransmitter and molecular pathways. These changes shape the functioning of the neural circuits that regulate reward, fear, emotion reactivity and social behaviour, which together are thought to mediate successful coping with stress.

Key Points The axon initial segment (AIS) functions as both a structural and a functional bridge between neuronal input and output. The AIS is characterized by clustered voltage-gated Na + and K + channels that integrate synaptic inputs and initiate action potentials. The AIS also has high densities of cell adhesion molecules, signalling proteins and cytoskeletal proteins and scaffolds. The AIS regulates three kinds of neuronal polarity: functional polarity (that is, the directional propagation of information), anatomical polarity (that is, the distinction between axonal and somatodendritic domains) and subcellular polarity (that is, the restricted localization of ion channels, organelles and protein complexes to distinct membrane domains or cellular compartments). The assembly of the AIS protein complexes and establishment of AIS subcellular polarity depends on the cytoskeletal scaffolding protein ankyrin G (AnkG, also known as ANK3). Thus, AnkG is the master organizer of the AIS. The maintenance of neuronal polarity depends on a physical barrier that is located at the AIS and restricts lipids, membrane and cytoplasmic proteins and vesicular cargoes to somatodendritic or axonal domains. Actin, microtubules and the high density of proteins at the AIS all contribute to this barrier. AnkG is also required for the functioning of the barrier, including the regulation of actin and microtubules and protein retention at the AIS. Loss of AnkG results in dismantling of the AIS and the axon acquiring the structural and molecular properties of dendrites. The AIS cytoskeleton can be disrupted by diseases and injuries, causing loss of clustered ion channels and anatomical polarity. Loss of neuronal polarity may be a previously overlooked consequence of nervous system injury. The AIS can be viewed as the 'gatekeeper' of nervous system function, and the modulation of AIS properties can have dramatic consequences for neuronal excitability and circuit properties. Neuronal activity can modulate the location of the AIS, which in turn influences the input–output response of the neuron. In contrast to synaptic plasticity, AIS plasticity occurs over hours and even days, and therefore may result in changes to the neuronal input–output function that persist over long periods of time. Polarity is an essential requirement for neuronal function. Matthew Rasband describes the role of the axon initial segment in the development and maintenance of neuronal polarity and discusses how its disruption can lead to disorders of the nervous system. Ion channel clustering at the axon initial segment (AIS) and nodes of Ranvier has been suggested to be a key evolutionary innovation that enabled the development of the complex vertebrate nervous system. This innovation epitomizes a signature feature of neurons, namely polarity. The mechanisms that establish neuronal polarity, channel clustering and axon–dendrite identity during development are becoming clearer. However, much less is known about how polarity is maintained throughout life. Here, I review the role of the AIS in the development and maintenance of neuronal polarity and discuss how disrupted polarity may be a common component of many diseases and injuries that affect the nervous system.

The maintenance of a progenitor cell population as a reservoir of undifferentiated cells is required for organ development and regeneration. However, the mechanisms by which epithelial progenitor cells are maintained during organogenesis are poorly understood. We report that removal of the parasympathetic ganglion in mouse explant organ culture decreased the number and morphogenesis of keratin 5-positive epithelial progenitor cells. These effects were rescued with an acetylcholine analog. We demonstrate that acetylcholine signaling, via the muscarinic M1 receptor and epidermal growth factor receptor, increased epithelial morphogenesis and proliferation of the keratin 5-positive progenitor cells. Parasympathetic innervation maintained the epithelial progenitor cell population in an undifferentiated state, which was required for organogenesis. This mechanism for epithelial progenitor cell maintenance may be targeted for organ repair or regeneration.

Quantifying cell behaviors in animal early embryogenesis remains a challenging issue requiring in toto imaging and automated image analysis. We designed a framework for imaging and reconstructing unstained whole zebrafish embryos for their first 10 cell division cycles and report measurements along the cell lineage with micrometer spatial resolution and minute temporal accuracy. Point-scanning multiphoton excitation optimized to preferentially probe the innermost regions of the embryo provided intrinsic signals highlighting all mitotic spindles and cell boundaries. Automated image analysis revealed the phenomenology of cell proliferation. Blastomeres continuously drift out of synchrony. After the 32-cell stage, the cell cycle lengthens according to cell radial position, leading to apparent division waves. Progressive amplification of this process is the rule, contrasting with classical descriptions of abrupt changes in the system dynamics.

After fertilization, maternal proteins in oocytes are degraded and new proteins encoded by the zygotic genome are synthesized. We found that autophagy, a process for the degradation of cytoplasmic constituents in the lysosome, plays a critical role during this period. Autophagy was triggered by fertilization and up-regulated in early mouse embryos. Autophagy-defective oocytes derived from oocyte-specific Atg5 (autophagy-related 5) knockout mice failed to develop beyond the four- and eight-cell stages if they were fertilized by Atg5-null sperm, but could develop if they were fertilized by wild-type sperm. Protein synthesis rates were reduced in the autophagy-null embryos. Thus, autophagic degradation within early embryos is essential for preimplantation development in mammals.

Angiogenesis: grow with the flow During embryogenesis, blood vessels are remodelled in response to blood flow. Nicoli et al . describe a genetic pathway that explains how this mechanosensory stimulus is integrated with early developmental signals to remodel aortic arch vessels in zebrafish. The flow-induced transcription factor klf2a is required for the induction of an endothelial cell-specific microRNA, miR-126 , which promotes VEGF signalling and angiogenesis through repressing Spred1 , an inhibitor of VEGF signalling. This demonstrates how blood flow modulates endothelial cell-signalling pathways and implicates a microRNA as a central integration point during this process. During embryonic development, blood vessels remodel in response to blood flow. Here, a genetic pathway is described through which this mechanosensory stimulus is integrated with early developmental signals to remodel vessels of the aortic arch in zebrafish. It is found that the flow-induced transcription factor klf2a is required to induce the expression of an endothelial-specific microRNA, activating signalling through the growth factor Vegf. Within the circulatory system, blood flow regulates vascular remodelling 1 , stimulates blood stem cell formation 2 , and has a role in the pathology of vascular disease 3 . During vertebrate embryogenesis, vascular patterning is initially guided by conserved genetic pathways that act before circulation 4 . Subsequently, endothelial cells must incorporate the mechanosensory stimulus of blood flow with these early signals to shape the embryonic vascular system 4 . However, few details are known about how these signals are integrated during development. To investigate this process, we focused on the aortic arch (AA) blood vessels, which are known to remodel in response to blood flow 1 . By using two-photon imaging of live zebrafish embryos, we observe that flow is essential for angiogenesis during AA development. We further find that angiogenic sprouting of AA vessels requires a flow-induced genetic pathway in which the mechano-sensitive zinc finger transcription factor klf2a 5 , 6 , 7 induces expression of an endothelial-specific microRNA, mir-126 , to activate Vegf signalling. Taken together, our work describes a novel genetic mechanism in which a microRNA facilitates integration of a physiological stimulus with growth factor signalling in endothelial cells to guide angiogenesis.

Unidirectional fluid flow plays an essential role in the breaking of left-right (L-R) symmetry in mouse embryos, but it has remained unclear how the flow is sensed by the embryo. We report that the Ca²⁺ channel Polycystin-2 (Pkd2) is required specifically in the perinodal crown cells for sensing the nodal flow. Examination of mutant forms of Pkd2 shows that the ciliary localization of Pkd2 is essential for correct L-R patterning. Whereas Kif3a mutant embryos, which lack all cilia, failed to respond to an artificial flow, restoration of primary cilia in crown cells rescued the response to the flow. Our results thus suggest that nodal flow is sensed in a manner dependent on Pkd2 by the cilia of crown cells located at the edge of the node.