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An essential prerequisite for the survival of an organism is the ability to detect and respond to aversive stimuli. Current belief is that noxious stimuli directly activate nociceptive sensory nerve endings in the skin. We discovered a specialized cutaneous glial cell type with extensive processes forming a mesh-like network in the subepidermal border of the skin that conveys noxious thermal and mechanical sensitivity. We demonstrate a direct excitatory functional connection to sensory neurons and provide evidence of a previously unknown organ that has an essential physiological role in sensing noxious stimuli. Thus, these glial cells, which are intimately associated with unmyelinated nociceptive nerves, are inherently mechanosensitive and transmit nociceptive information to the nerve.

Cytoskeletal cords connecting cells at the back of cell groups enable directional migration Constructing multicellular bodies, starting from a single-cell zygote, often requires the movement of cells across considerable distances, which is achieved through cell migration. During embryonic development, as well as in healing and regeneration, cells travel across diverse terrains, which dictates the character of navigation ( 1 ). Cancer cells metastasize and migrate into healthy organs, and knowledge of their migration strategies could be important to identify targets to treat advanced disease ( 2 ). Some migratory cells cover large distances individually ( 3 ), whereas others migrate in groups, with leaders and followers being directed by chemical signals (chemotaxis) ( 4 , 5 ). The exchange of information and resulting motility of such groups has been enigmatic. Moreover, the driving force of collective cell migration has been considered a sum of migratory and signaling activities of individually participating cells. However, according to a study on page 339 of this issue by Shellard et al. ( 6 ), collective cell migration requires formation of cytoskeletal structures that span through adjoining cells at the rear of a cell group to coordinate, orient, and propel the entire group. This mechanism of collective cell migration could be applicable to cancer metastasis and wound healing and might change our understanding of developmental migration.

Different types of spiral ganglion neurons (SGNs) are essential for auditory perception by transmitting complex auditory information from hair cells (HCs) to the brain. Here, we use deep, single cell transcriptomics to study the molecular mechanisms that govern their identity and organization in mice. We identify a core set of temporally patterned genes and gene regulatory networks that may contribute to the diversification of SGNs through sequential binary decisions and demonstrate a role for NEUROD1 in driving specification of a I c -SGN phenotype. We also find that each trajectory of the decision tree is defined by initial co-expression of alternative subtype molecular controls followed by gradual shifts toward cell fate resolution. Finally, analysis of both developing SGN and HC types reveals cell-cell signaling potentially playing a role in the differentiation of SGNs. Our results indicate that SGN identities are drafted prior to birth and reveal molecular principles that shape their differentiation and will facilitate studies of their development, physiology, and dysfunction. This study chronicles dynamic gene expression in differentiating spiral ganglion neurons from murine embryonic day 14.5 to postnatal stage, establishes their lineage trajectories, and identifies molecular determinants of cell fate decision.

Branching morphogenesis governs the formation of many organs such as lung, kidney, and the neurovascular system. Many studies have explored system-specific molecular and cellular regulatory mechanisms, as well as self-organizing rules underlying branching morphogenesis. However, in addition to local cues, branched tissue growth can also be influenced by global guidance. Here, we develop a theoretical framework for a stochastic self-organized branching process in the presence of external cues. Combining analytical theory with numerical simulations, we predict differential signatures of global vs. local regulatory mechanisms on the branching pattern, such as angle distributions, domain size, and space-filling efficiency. We find that branch alignment follows a generic scaling law determined by the strength of global guidance, while local interactions influence the tissue density but not its overall territory. Finally, using zebrafish innervation as a model system, we test these key features of the model experimentally. Our work thus provides quantitative predictions to disentangle the role of different types of cues in shaping branched structures across scales. Many organs and cells have complex tree-like morphologies, but how these patterns emerge during development from global guidance cues and local self-organization remains unclear. Here, the authors develop a theory for the influence of both factors and test it on neuronal branching data.

The adrenal glands affect a variety of processes such as stress responses and metabolism. The mature adrenal gland is formed from multiple tissue sources, including cells of neural origin. Furlan et al. traced the origins of these cells. The cells first become Schwann cell precursors and follow along nerves to travel from the dorsal root ganglia of the spine to the adrenal gland. Once there, the cells differentiate into chromaffin cells. The authors used singlecell transcriptomics to reveal the shifts in functional programs during migration, development, and differentiation. Science , this issue p. eaal3753 The adrenal gland is built from cells that travel along highways of nerves. Adrenaline is a fundamental circulating hormone for bodily responses to internal and external stressors. Chromaffin cells of the adrenal medulla (AM) represent the main neuroendocrine adrenergic component and are believed to differentiate from neural crest cells. We demonstrate that large numbers of chromaffin cells arise from peripheral glial stem cells, termed Schwann cell precursors (SCPs). SCPs migrate along the visceral motor nerve to the vicinity of the forming adrenal gland, where they detach from the nerve and form postsynaptic neuroendocrine chromaffin cells. An intricate molecular logic drives two sequential phases of gene expression, one unique for a distinct transient cellular state and another for cell type specification. Subsequently, these programs down-regulate SCP-gene and up-regulate chromaffin cell–gene networks. The AM forms through limited cell expansion and requires the recruitment of numerous SCPs. Thus, peripheral nerves serve as a stem cell niche for neuroendocrine system development.

Somatic sensation is defined by the existence of a diversity of primary sensory neurons with unique biological features and response profiles to external and internal stimuli. However, there is no coherent picture about how this diversity of cell states is transcriptionally generated. Here, we use deep single cell analysis to resolve fate splits and molecular biasing processes during sensory neurogenesis in mice. Our results identify a complex series of successive and specific transcriptional changes in post-mitotic neurons that delineate hierarchical regulatory states leading to the generation of the main sensory neuron classes. In addition, our analysis identifies previously undetected early gene modules expressed long before fate determination although being clearly associated with defined sensory subtypes. Overall, the early diversity of sensory neurons is generated through successive bi-potential intermediates in which synchronization of relevant gene modules and concurrent repression of competing fate programs precede cell fate stabilization and final commitment. The diversity of primary sensory neurons and how fate choice is determined is unclear. Here, the authors use single cell RNA sequencing analysis of early murine somatosensory neurons to show that sensory neuron diversity is achieved by a transition through a bi-potential intermediate state.

During early development, cartilage provides shape and stability to the embryo while serving as a precursor for the skeleton. Correct formation of embryonic cartilage is hence essential for healthy development. In vertebrate cranial cartilage, it has been observed that a flat and laterally extended macroscopic geometry is linked to regular microscopic structure consisting of tightly packed, short, transversal clonar columns. However, it remains an ongoing challenge to identify how individual cells coordinate to successfully shape the tissue, and more precisely which mechanical interactions and cell behaviors contribute to the generation and maintenance of this columnar cartilage geometry during embryogenesis. Here, we apply a three-dimensional cell-based computational model to investigate mechanical principles contributing to column formation. The model accounts for clonal expansion, anisotropic proliferation and the geometrical arrangement of progenitor cells in space. We confirm that oriented cell divisions and repulsive mechanical interactions between cells are key drivers of column formation. In addition, the model suggests that column formation benefits from the spatial gaps created by the extracellular matrix in the initial configuration, and that column maintenance is facilitated by sequential proliferative phases. Our model thus correctly predicts the dependence of local order on division orientation and tissue thickness. The present study presents the first cell-based simulations of cell mechanics during cranial cartilage formation and we anticipate that it will be useful in future studies on the formation and growth of other cartilage geometries.

The complex shape of embryonic cartilage represents a true challenge for phenotyping and basic understanding of skeletal development. X-ray computed microtomography (μCT) enables inspecting relevant tissues in all three dimensions; however, most 3D models are still created by manual segmentation, which is a time-consuming and tedious task. In this work, we utilised a convolutional neural network (CNN) to automatically segment the most complex cartilaginous system represented by the developing nasal capsule. The main challenges of this task stem from the large size of the image data (over a thousand pixels in each dimension) and a relatively small training database, including genetically modified mouse embryos, where the phenotype of the analysed structures differs from the norm. We propose a CNN-based segmentation model optimised for the large image size that we trained using a unique manually annotated database. The segmentation model was able to segment the cartilaginous nasal capsule with a median accuracy of 84.44% (Dice coefficient). The time necessary for segmentation of new samples shortened from approximately 8 h needed for manual segmentation to mere 130 s per sample. This will greatly accelerate the throughput of μCT analysis of cartilaginous skeletal elements in animal models of developmental diseases.

Endomesoderm specification by a maternal β-catenin signal and body axis patterning by interpreting a gradient of zygotic Wnt/β-catenin signalling was suggested to predate the split between Bilateria and their sister clade Cnidaria. However, in Cnidaria, the roles of β-catenin signalling in these processes have not been demonstrated directly. Here, by tagging the endogenous β-catenin in the cnidarian Nematostella vectensis , we confirm that its oral-aboral axis is indeed patterned by a gradient of β-catenin signalling. Strikingly, we show that, in contrast to bilaterians, Nematostella endomesoderm specification is repressed by β-catenin and takes place in the maternal nuclear β-catenin-negative part of the embryo. This completely changes the accepted paradigm and suggests that β-catenin-dependent endomesoderm specification was a bilaterian innovation linking endomesoderm specification to the subsequent posterior-anterior patterning. Lebedeva et al . show that unlike Bilateria, the embryo of the cnidarian Nematostella specifies its endomesoderm in the β-catenin-negative domain. In contrast, subsequent β-catenin-dependent axial patterning acts similarly in Cnidaria and Bilateria.

Immature multipotent embryonic peripheral glial cells, the Schwann cell precursors (SCPs), differentiate into melanocytes, parasympathetic neurons, chromaffin cells, and dental mesenchymal populations. Here, genetic lineage tracing revealed that, during murine embryonic development, some SCPs detach from nerve fibers to become mesenchymal cells, which differentiate further into chondrocytes and mature osteocytes. This occurred only during embryonic development, producing numerous craniofacial and trunk skeletal elements, without contributing to development of the appendicular skeleton. Formation of chondrocytes from SCPs also occurred in zebrafish, indicating evolutionary conservation. Our findings reveal multipotency of SCPs, providing a developmental link between the nervous system and skeleton.