Current Topics in Developmental Biology最新文献

Meiosis increases genetic diversity in offspring by generating genetically unique haploid gametes with reshuffled chromosomes. This process requires a specialized set of meiotic proteins, which facilitate chromosome recombination and segregation. However, re-expression of meiotic proteins in mitosis can have catastrophic oncogenic consequences and aberrant expression of meiotic proteins is a common occurrence in human tumors. Mechanistically, re-activation of meiotic genes in cancer promotes oncogenesis likely because cancers-conversely to healthy mitosis-are fueled by genetic instability which promotes tumor evolution, and evasion of immune response and treatment pressure. In this review, we explore similarities between meiotic and cancer cells with a particular focus on the oncogenic activation of meiotic genes in cancer. We emphasize the role of histones and their modifications, DNA methylation, genome organization, R-loops and the availability of distal enhancers.

The role of Wnt signaling in stem cells has been mired in seemingly contradictory findings. On one hand, Wnt has been heralded as a self-renewal factor. On the other hand, Wnt's association with differentiation and lineage commitment is indisputable. This apparent contradiction is particularly evident in pluripotent stem cells, where Wnt promotes self-renewal as well as differentiation. To resolve this discrepancy one must delve into fundamental principles of pluripotency and gain an appreciation for the concept of pluripotency states, which exist in a continuum with intermediate metastable states, some of which have been stabilized in vitro. Wnt signaling is a critical regulator of transitions between pluripotent states. Here, we will discuss Wnt's roles in maintaining pluripotency, promoting differentiation, as well as stimulating reprogramming of somatic cells to an induced pluripotent state.

Immune cells are responsible for pathogen detection and elimination, as well as for signaling to other cells the presence of potential danger. In order to mount an efficient immune response, they need to move and search for a pathogen, interact with other cells, and diversify the population by asymmetric cell division. All these actions are regulated by cell polarity: cell polarity controls cell motility, which is crucial for scanning peripheral tissues to detect pathogens, and recruiting immune cells to sites of infection; immune cells, in particular lymphocytes, communicate with each other by a direct contact called immunological synapse, which entails a global polarization of the cell and plays a role in activating lymphocyte response; finally, immune cells divide asymmetrically from a precursor, generating a diversity of phenotypes and cell types among daughter cells, such as memory and effector cells. This review aims at providing an overview from both biology and physics perspectives of how cell polarity shapes the main immune cell functions.

Craniofacial anomalies often exhibit phenotype variability and non-mendelian inheritance due to their multifactorial origin, involving both genetic and environmental factors. A combination of epidemiologic studies, genome-wide association, and analysis of animal models have provided insight into the effects of gene-environment interactions on craniofacial and brain development and the pathogenesis of congenital disorders. In this chapter, we briefly summarize the etiology and pathogenesis of common craniofacial anomalies, focusing on orofacial clefts, hemifacial microsomia, and microcephaly. We then discuss how environmental risk factors interact with genes to modulate the incidence and phenotype severity of craniofacial anomalies. Identifying environmental risk factors and dissecting their interaction with different genes and modifiers is central to improved strategies for preventing craniofacial anomalies.

Wnts are secreted proteins that control stem cell maintenance, cell fate decisions, and growth during development and adult homeostasis. Wnts carry a post-translational modification not seen in any other secreted protein: during biosynthesis, they are appended with a palmitoleoyl moiety that is required for signaling but also impairs solubility and hence diffusion in the extracellular space. In some contexts, Wnts act only in a juxtacrine manner but there are also instances of long range action. Several proteins and processes ensure that active Wnts reach the appropriate target cells. Some, like Porcupine, Wntless, and Notum are dedicated to Wnt function; we describe their activities in molecular detail. We also outline how the cell infrastructure (secretory, endocytic, and retromer pathways) contribute to the progression of Wnts from production to delivery. We then address how Wnts spread in the extracellular space and form a signaling gradient despite carrying a hydrophobic moiety. We highlight particularly the role of lipid-binding Wnt interactors and heparan sulfate proteoglycans. Finally, we briefly discuss how evolution might have led to the emergence of this unusual signaling pathway.

Chromosomal transactions such as replication, recombination and segregation are monitored by cell cycle checkpoint cascades. These checkpoints ensure the proper execution of processes that are needed for faithful genome inheritance from one cell to the next, and across generations. In meiotic prophase, a specialized checkpoint monitors defining events of meiosis: programmed DNA break formation, followed by dedicated repair through recombination based on interhomolog (IH) crossovers. This checkpoint shares molecular characteristics with canonical DNA damage checkpoints active during somatic cell cycles. However, idiosyncratic requirements of meiotic prophase have introduced unique features in this signaling cascade. In this review, we discuss the unique features of the meiotic prophase checkpoint. While being related to canonical DNA damage checkpoint cascades, the meiotic prophase checkpoint also shows similarities with the spindle assembly checkpoint (SAC) that guards chromosome segregation. We highlight these emerging similarities in the signaling logic of the checkpoints that govern meiotic prophase and chromosome segregation, and how thinking of these similarities can help us better understand meiotic prophase control. We also discuss work showing that, when aberrantly expressed, components of the meiotic prophase checkpoint might alter DNA repair fidelity and chromosome segregation in cancer cells. Considering checkpoint function in light of demands imposed by the special characteristics of meiotic prophase helps us understand checkpoint integration into the meiotic cell cycle machinery.

Epithelia are tissues with diverse morphologies and functions across metazoans, ranging from vast cell sheets encasing internal organs to internal tubes facilitating nutrient uptake, all of which require establishment of apical-basolateral polarity axes. While all epithelia tend to polarize the same components, how these components are deployed to drive polarization is largely context-dependent and likely shaped by tissue-specific differences in development and ultimate functions of polarizing primordia. The nematode Caenorhabditis elegans (C. elegans) offers exceptional imaging and genetic tools and possesses unique epithelia with well-described origins and roles, making it an excellent model to investigate polarity mechanisms. In this review, we highlight the interplay between epithelial polarization, development, and function by describing symmetry breaking and polarity establishment in a particularly well-characterized epithelium, the C. elegans intestine. We compare intestinal polarization to polarity programs in two other C. elegans epithelia, the pharynx and epidermis, correlating divergent mechanisms with tissue-specific differences in geometry, embryonic environment, and function. Together, we emphasize the importance of investigating polarization mechanisms against the backdrop of tissue-specific contexts, while also underscoring the benefits of cross-tissue comparisons of polarity.

The epidermis is a stratified squamous epithelium that forms the outermost layer of the skin. Its primary function is to act as a barrier, keeping pathogens and toxins out and moisture in. This physiological role has necessitated major differences in the organization and polarity of the tissue as compared to simple epithelia. We discuss four aspects of polarity in the epidermis - the distinctive polarities of basal progenitor cells as well as differentiated granular cells, the polarity of adhesions and the cytoskeleton across the tissue as keratinocytes differentiate, and the planar cell polarity of the tissue. These distinctive polarities are essential for the morphogenesis and the function of the epidermis and have also been implicated in regulating tumor formation.

During embryo development, cell proliferation, cell fate specification and tissue patterning are coordinated and tightly regulated by a handful of evolutionarily conserved signaling pathways activated by secreted growth factor families including fibroblast growth factor (FGF), Nodal/bone morphogenetic protein (BMP), Hedgehog and Wnt. The spatial and temporal activation of these signaling pathways elicit context-specific cellular responses that ultimately shape the different tissues of the embryo. Extensive efforts have been dedicated to identifying the molecular mechanisms underlying these signaling pathways during embryo development, adult tissue homeostasis and regeneration. In this review, we first describe the role of the Wnt/β-catenin signaling pathway during early embryo development, axis specification and cell differentiation as a prelude to highlight how this knowledge is being leveraged to manipulate Wnt/β-catenin signaling activity with small molecules and biologics for the directed differentiation of pluripotent stem cells into various cell lineages that are physiologically relevant for stem cell therapy and regenerative medicine.

This chapter reviews the evidence of gene×environment interactions (G×E) in the etiology of orofacial cleft birth defects (OFCs), specifically cleft lip (CL), cleft palate (CP), and cleft lip with or without cleft palate (CL/P). We summarize the current state of our understanding of the genetic architecture of nonsyndromic OFCs and the evidence that maternal exposures during pregnancy influence risk of OFCs. Further, we present possible candidate gene pathways for these exposures including metabolism of folates, metabolism of retinoids, retinoic acid receptor signaling, aryl hydrocarbon receptor signaling, glucocorticoid receptor signaling, and biotransformation and transport. We review genes in these pathways with prior evidence of association with OFCs, genes with evidence from prior candidate gene G×E studies, and genes identified from genome-wide searches specifically for identifying G×E. Finally, we suggest future directions for G×E research in OFCs.