Current Topics in Developmental Biology最新文献

Crossover events during recombination in meiosis are essential for generating genetic diversity as well as crucial to allow accurate chromosomal segregation between homologous chromosomes. Spatial control for the distribution of crossover events along the chromosomes is largely a tightly regulated process and involves many facets such as interference, repression as well as assurance, to make sure that not too many or too few crossovers are generated. Repression of crossover events at the centromeres is a highly conserved process across all species tested. Failure to inhibit such recombination events can result in chromosomal mis-segregation during meiosis resulting in aneuploid gametes that are responsible for infertility or developmental disorders such as Down's syndrome and other trisomies in humans. In the past few decades, studies to understand the molecular mechanisms behind this repression have shown the involvement of a multitude of factors ranging from the centromere-specific proteins such as the kinetochore to the flanking pericentric heterochromatin as well as DNA double-strand break repair pathways. In this chapter, we review the different mechanisms of pericentric repression mechanisms known till date as well as highlight the importance of understanding this regulation in the context of chromosomal segregation defects. We also discuss the clinical implications of dysregulation of this process, especially in human reproductive health and genetic diseases.

Deciphering non-canonical WNT signaling has proven to be both fascinating and challenging. Discovered almost 30 years ago, non-canonical WNT ligands signal independently of the transcriptional co-activator β-catenin to regulate a wide range of morphogenetic processes during development. The molecular and cellular mechanisms that underlie non-canonical WNT function, however, remain nebulous. Recent results from various model systems have converged to define a core non-canonical WNT pathway consisting of the prototypic non-canonical WNT ligand, WNT5A, the receptor tyrosine kinase ROR, the seven transmembrane receptor Frizzled and the cytoplasmic scaffold protein Dishevelled. Importantly, mutations in each of these signaling components cause Robinow syndrome, a congenital disorder characterized by profound tissue morphogenetic abnormalities. Moreover, dysregulation of the pathway has also been linked to cancer metastasis. As new knowledge concerning the WNT5A-ROR pathway continues to grow, modeling these mutations will likely provide crucial insights into both the physiological regulation of the pathway and the etiology of WNT5A-ROR-driven diseases.

Wnt signaling plays essential roles in multiple steps of left-right (L-R) determination in development. First, canonical Wnt signaling is required to form the node, where L-R symmetry breaking takes place. Secondly, planar cell polarity (PCP) driven by non-canonical Wnt signaling polarizes node cells along the anterio-posterior (A-P) axis and provides the tilt of rotating cilia at the node, which generate the leftward fluid flow. Thus, reciprocal expression of Wnt5a/5b and their inhibitors Sfrp1, 2, 5 generates a gradient of Wnt5 activity along the embryo's anterior-posterior (A-P) axis. This polarizes cells at the node, by placing PCP core proteins on the anterior or posterior side of each node cell. Polarized PCP proteins subsequently induce asymmetric organization of microtubules along the A-P axis, which is thought to push the centrally localized basal body toward the posterior side of a node cell. Motile cilia that extend from the posteriorly-shifted basal body is tilted toward the posterior side of the embryo. Thirdly, canonical-Wnt signaling regulates the level and expansion of Nodal activity and establishes L-R asymmetric Nodal activity at the node, the first molecular asymmetry in the mouse embryo. Overall, both canonical and non-canonical Wnt signalings are essential for L-R symmetry breaking.

Regeneration abilities are widespread among animals and select species can restore any body parts removed by wounds that sever the major body axes. This capability of whole-body regeneration as exemplified in flatworm planarians, Acoels, and Cnidarians involves initial responses to injury, the assessment of wound site polarization, determination of missing tissue and programming of blastema fate, and patterned outgrowth to restore axis content and proportionality. Wnt signaling drives many shared and conserved aspects of the biology of whole-body regeneration in the planarian species Schmidtea mediterranea and Dugesia japonica, in the Acoel Hofstenia miamia, and in Cnidarians Hydra and Nematostella. These overlapping mechanisms suggest whole-body regeneration might be an ancestral property across diverse animal taxa.

Wnt family proteins are secreted glycolipoproteins that signal through multitude of signal transduction pathways. The Wnt-pathways are conserved and critical in all metazoans. They are essential for embryonic development, organogenesis and homeostasis, and associated with many diseases when defective or deregulated. Wnt signaling pathways comprise the canonical Wnt pathway, best known for its stabilization of β-catenin and associated nuclear β-catenin activity in gene regulation, and several non-canonical signaling branches. Wnt-Planar Cell Polarity (PCP) signaling has received the most attention among the non-canonical Wnt pathways. The relationship of cilia to Wnt-signaling is complex. While it was suggested that canonical Wnt signaling requires cilia this notion was always challenged by results suggesting the opposite. Recent developments provide insight and clarification to the relationship of Wnt signaling pathways and cilia. First, it has been now demonstrated that while ciliary proteins, in particular the IFT-A complex, are required for canonical Wnt/β-catenin signaling, the cilium as a structure is not. In contrast, recent work has defined a diverged canonical signaling branch (not affecting β-catenin) to be required for ciliary biogenesis and cilia function. Furthermore, the non-canonical Wnt-PCP pathway does not affect cilia biogenesis per se, but it regulates the position of cilia within cells in many cell types, possibly in all cells where it is active, with cilia being placed near the side of the cell that has the Frizzled-Dishevelled complex. This Wnt/PCP feature is conserved with both centrioles and basal bodies/cilia being positioned accordingly, and it is also used to align mitotic spindles within the Wnt-PCP polarization axis. It also coordinates the alignment of cilia in multiciliated cells. This article addresses these new insights and different links and relationships between cilia and Wnt signaling.

Primary cilia are specialized organelles on the surface of almost all cells in vertebrate tissues and are primarily involved in the detection of extracellular stimuli. In retinal photoreceptors, cilia are uniquely modified to form outer segments containing components required for the detection of light in stacks of membrane discs. Not surprisingly, vision impairment is a frequent phenotype associated with ciliopathies, a heterogeneous class of conditions caused by mutations in proteins required for formation, maintenance and/or function of primary cilia. Traditionally, immortalized cell lines and model organisms have been used to provide insights into the biology of ciliopathies. The advent of methods for reprogramming human somatic cells into pluripotent stem cells has enabled the generation of in vitro disease models directly from patients suffering from ciliopathies. Such models help us in investigating pathological mechanisms specific to human physiology and in developing novel therapeutic approaches. In this article, we review current protocols to differentiate human pluripotent stem cells into retinal cell types, and discuss how these cellular and/or organoid models can be utilized to interrogate pathobiology of ciliopathies affecting the retina and for testing prospective treatments.

Successful meiosis I requires that homologous chromosomes be correctly linked before they are segregated. In most organisms this physical linkage is achieved through the generation of crossovers between the homologs. Meiotic recombination co-opts and modifies the canonical homologous recombination pathway to successfully generate crossovers One of the central components of this pathway are a number of conserved DNA helicases. Helicases couple nucleic acid binding to nucleotide hydrolysis and use this activity to modify DNA or protein-DNA substrates. During meiosis I it is necessary for the cell to modulate the canonical DNA repair pathways in order to facilitate the generation of interhomolog crossovers. Many of these meiotic modulations take place in pathways involving DNA helicases, or with a meiosis specific helicase. This short review explores what is currently understood about these helicases, their interaction partners, and the role of regulatory modifications during meiosis I. We focus in particular on the molecular structure and mechanisms of these helicases.

Sexual reproduction and the specialized cell division it relies upon, meiosis, are biological processes that present an incredible degree of both evolutionary conservation and divergence. One clear example of this paradox is the role of the evolutionarily ancient PCH-2/HORMAD module during meiosis. On one hand, the complex, and sometimes disparate, meiotic defects observed when PCH-2 and/or the meiotic HORMADS are mutated in different model systems have prevented a straightforward characterization of their conserved functions. On the other hand, these functional variations demonstrate the impressive molecular rewiring that accompanies evolution of the meiotic processes these factors are involved in. While the defects observed in pch-2 mutants appear to vary in different systems, in this review, I argue that PCH-2 has a conserved meiotic function: to coordinate meiotic recombination with synapsis to ensure an appropriate number and distribution of crossovers. Further, given the dramatic variation in how the events of recombination and synapsis are themselves regulated in different model systems, the mechanistic differences in PCH-2 and meiotic HORMAD function make biological sense when viewed as species-specific elaborations layered onto this fundamental, conserved role.

The barrier function of epithelia is one of the cornerstones of the body plan organization of metazoans. It relies on the polarity of epithelial cells which organizes along the apico-basal axis the mechanical properties, signaling as well as transport. This barrier function is however constantly challenged by the fast turnover of epithelia occurring during morphogenesis or adult tissue homeostasis. Yet, the sealing property of the tissue can be maintained thanks to cell extrusion: a series of remodeling steps involving the dying cell and its neighbors leading to seamless cell expulsion. Alternatively, the tissue architecture can also be challenged by local damages or the emergence of mutant cells that may alter its organization. This includes mutants of the polarity complexes which can generate neoplastic overgrowths or be eliminated by cell competition when surrounded by wild type cells. In this review, we will provide an overview of the regulation of cell extrusion in various tissues focusing on the relationship between cell polarity, cell organization and the direction of cell expulsion. We will then describe how local perturbations of polarity can also trigger cell elimination either by apoptosis or by cell exclusion, focusing specifically on how polarity defects can be directly causal to cell elimination. Overall, we propose a general framework connecting the influence of polarity on cell extrusion and its contribution to aberrant cell elimination.