Current Topics in Developmental Biology最新文献

Muscle stem cells (MuSCs) are crucial to the repair and homeostasis of mature skeletal muscle. MuSC dysfunction and dysregulation of the myogenic program can contribute to the development of pathology ranging from cancers like rhabdomyosarcoma (RMS) or muscle degenerative diseases such as Duchenne muscular dystrophy (DMD). Both diseases exhibit dysregulation at nearly all steps of myogenesis. For instance, MuSC self-renewal processes are altered. In RMS, this leads to the creation of tumor propagating cells. In DMD, impaired asymmetric stem cell division creates a bias towards producing self-renewing stem cells instead of committing to differentiation. Hyperproliferation of these cells contribute to tumorigenesis in RMS and symmetric expansion of the self-renewing MuSC population in DMD. Both diseases also exhibit a repression of factors involved in terminal differentiation, halting RMS cells in the proliferative stage and thus driving tumor growth. Conversely, the MuSCs in DMD exhibit impaired differentiation and fuse prematurely, affecting myonuclei maturation and the integrity of the dystrophic muscle fiber. Finally, both disease states cause alterations to the MuSC niche. Various elements of the niche such as inflammatory and migratory signaling that impact MuSC behavior are dysregulated. Here we show how these seemingly distantly related diseases indeed have similarities in MuSC dysfunction, underlying the importance of considering MuSCs when studying the pathophysiology of muscle diseases.

Morphogenesis from cells to tissue gives rise to the complex architectures that make our organs. How cells and their dynamic behavior are translated into functional spatial patterns is only starting to be understood. Recent advances in quantitative imaging revealed that, although highly heterogeneous, cellular behaviors make reproducible tissue patterns. Emerging evidence suggests that mechanisms of cellular coordination, intrinsic variability and plasticity are critical for robust pattern formation. While pattern development shows a high level of fidelity, tissue organization has undergone drastic changes throughout the course of evolution. In addition, alterations in cell behavior, if unregulated, can cause developmental malformations that disrupt function. Therefore, comparative studies of different species and of disease models offer a powerful approach for understanding how novel spatial configurations arise from variations in cell behavior and the fundamentals of successful pattern formation. In this chapter, I dive into the development of the vertebrate nervous system to explore efforts to dissect pattern formation beyond molecules, the emerging core principles and open questions.

External bilateral symmetry is a prevalent feature in vertebrates, which emerges during early embryonic development. To begin with, vertebrate embryos are largely radially symmetric before transitioning to bilaterally symmetry, after which, morphogenesis of various bilateral tissues (e.g somites, otic vesicle, limb bud), and structures (e.g palate, jaw) ensue. While a significant amount of work has probed the mechanisms behind symmetry breaking in the left-right axis leading to asymmetric positioning of internal organs, little is known about how bilateral tissues emerge at the same time with the same shape and size and at the same position on the two sides of the embryo. By discussing emergence of symmetry in many bilateral tissues and structures across vertebrate model systems, we highlight that understanding symmetry establishment is largely an open field, which will provide deep insights into fundamental problems in developmental biology for decades to come.

The Segmentation Clock is a tissue-level patterning system that enables the segmentation of the vertebral column precursors into transient multicellular blocks called somites. This patterning system comprises a set of elements that are essential for correct segmentation. Under the so-called "Clock and Wavefront" model, the system consists of two elements, a genetic oscillator that manifests itself as traveling waves of gene expression, and a regressing wavefront that transforms the temporally periodic signal encoded in the oscillations into a permanent spatially periodic pattern of somite boundaries. Over the last twenty years, every new discovery about the Segmentation Clock has been tightly linked to the nomenclature of the "Clock and Wavefront" model. This constrained allocation of discoveries into these two elements has generated long-standing debates in the field as what defines molecularly the wavefront and how and where the interaction between the two elements establishes the future somite boundaries. In this review, we propose an expansion of the "Clock and Wavefront" model into three elements, "Clock", "Wavefront" and signaling gradients. We first provide a detailed description of the components and regulatory mechanisms of each element, and we then examine how the spatiotemporal integration of the three elements leads to the establishment of the presumptive somite boundaries. To be as exhaustive as possible, we focus on the Segmentation Clock in zebrafish. Furthermore, we show how this three-element expansion of the model provides a better understanding of the somite formation process and we emphasize where our current understanding of this patterning system remains obscure.

Recent research has highlighted an important role for the molecular circadian machinery in the regulation of tissue-specific function and stress responses. Indeed, disruption of circadian function, which is pervasive in modern society, is linked to accelerated aging, obesity, and type 2 diabetes. Furthermore, evidence supporting the importance of the circadian clock within both the mature muscle tissue and satellite cells to regulate the maintenance of muscle mass and repair capacity in response injury has recently emerged. Here, we review the discovery of circadian clocks within the satellite cell (a.k.a. adult muscle stem cell) and how they act to regulate metabolism, epigenetics, and myogenesis during both healthy and diseased states.

A simple machine is a basic of device that takes mechanical advantage to apply force. Animals and plants self-assemble through the operation of a wide variety of simple machines. Embryos of different species actuate these simple machines to drive the geometric transformations that convert a disordered mass of cells into organized structures with discrete identities and function. These transformations are intrinsically coupled to sequential and overlapping steps of self-organization and self-assembly. The processes of self-organization have been explored through the molecular composition of cells and tissues and their information networks. By contrast, efforts to understand the simple machines underlying self-assembly must integrate molecular composition with the physical principles of mechanics. This primer is concerned with effort to elucidate the operation of these machines, focusing on the "problem" of morphogenesis. Advances in understanding self-assembly will ultimately connect molecular-, subcellular-, cellular- and meso-scale functions of plants and animals and their ability to interact with larger ecologies and environmental influences.

The salivary gland undergoes branching morphogenesis to elaborate into a tree-like structure with numerous saliva-secreting acinar units, all joined by a hierarchical ductal system. The expansive epithelial surface generated by branching morphogenesis serves as the structural basis for the efficient production and delivery of saliva. Here, we elucidate the process of salivary gland morphogenesis, emphasizing the role of mechanics. Structurally, the developing salivary gland is characterized by a stratified epithelium tightly encased by the basement membrane, which is in turn surrounded by a mesenchyme consisting of a dense network of interstitial matrix and mesenchymal cells. Diverse cell types and extracellular matrices bestow this developing organ with organized, yet spatially varied mechanical properties. For instance, the surface epithelial sheet of the bud is highly fluidic due to its high cell motility and weak cell-cell adhesion, rendering it highly pliable. In contrast, the inner core of the bud is more rigid, characterized by reduced cell motility and strong cell-cell adhesion, which likely provide structural support for the tissue. The interactions between the surface epithelial sheet and the inner core give rise to budding morphogenesis. Furthermore, the basement membrane and the mesenchyme offer mechanical constraints that could play a pivotal role in determining the higher-order architecture of a fully mature salivary gland.

Skeletal muscle stem cells (MuSCs), also known as satellite cells, are essential for muscle growth and injury induced regeneration. In healthy adult muscle, MuSCs remain in a quiescent state located in a specialized niche beneath the basal lamina. Upon injury, these dormant MuSCs can quickly activate to re-enter the cell cycle and differentiate into new myofibers, while a subset undergoes self-renewal and returns to quiescence to restore the stem cell pool. The myogenic lineage progression is intricately controlled by complex intrinsic and extrinsic cues and coupled with dynamic transcriptional programs. In transcriptional regulation, enhancers are key regulatory elements controlling spatiotemporal gene expression through physical contacting promoters of target genes. The three-dimensional (3D) chromatin architecture is known to orchestrate the establishment of proper enhancer-promoter interactions throughout development and aging. However, studies dissecting the 3D organization of enhancers in MuSCs are just emerging. Here, we provide an overview of the general properties of enhancers and newly developed methods for assessing their activity. In particular, we summarize recent discoveries regarding the 3D rewiring of enhancers during MuSC specification, lineage progression as well as aging.

The process of skeletal muscle regeneration involves a coordinated interplay of specific cellular and molecular interactions within the injury site. This review provides an overview of the cellular and molecular components in regenerating skeletal muscle, focusing on how these cells or molecules in the niche regulate muscle stem cell functions. Dysfunctions of muscle stem cell-to-niche cell communications during aging and disease will also be discussed. A better understanding of how niche cells coordinate with muscle stem cells for muscle repair will greatly aid the development of therapeutic strategies for treating muscle-related disorders.

Myocyte fusion is a pivotal process in the development and regeneration of skeletal muscle. Failure during fusion can lead to a range of developmental as well as pathological consequences. This review aims to comprehensively explore the intricate processes underlying myocyte fusion, from the molecular to tissue scale. We shed light on key players, such as the muscle-specific fusogens - Myomaker and Myomixer, in addition to some lesser studied molecules contributing to myocyte fusion. Conserved across vertebrates, Myomaker and Myomixer play a crucial role in driving the merger of plasma membranes of fusing myocytes, ensuring the formation of functional muscle syncytia. Our multiscale approach also delves into broader cell and tissue dynamics that orchestrate the timing and positioning of fusion events. In addition, we explore the relevance of muscle fusogens to human health and disease. Mutations in fusogen genes have been linked to congenital myopathies, providing unique insights into the molecular basis of muscle diseases. We conclude with a discussion on potential therapeutic avenues that may emerge from manipulating the myocyte fusion process to remediate skeletal muscle disorders.