BMP signaling and early embryonic patterning

Bone morphogenetic proteins (BMPs) play pleiotropic roles during embryonic development as well as throughout life. Recent genetic approaches especially using the mouse gene knockout system revealed that BMP signaling is greatly involved in early embryonic patterning, which is a dynamic event to establish three-dimensional polarities. The purpose of this review is to describe the diverse function of BMPs through different receptor signaling systems during embryonic patterning including gastrulation and establishment of the left-right asymmetry.     

Nodal signaling: developmental roles and regulation

Nodal-related ligands of the transforming growth factor-beta (TGFbeta) superfamily play central roles in patterning the early embryo during the induction of mesoderm and endoderm and the specification of left-right asymmetry. Additional roles for this pathway in the maintenance of embryonic stem cell pluripotency and in carcinogenesis have been uncovered more recently. Consistent with its crucial developmental functions, Nodal signaling is tightly regulated by diverse mechanisms including the control of ligand processing, utilization of co-receptors, expression of soluble antagonists, as well as positive- and negative-feedback activities.     

Mitochondrial redox systems as central hubs in plant metabolism and signaling

Plant mitochondria are indispensable for plant metabolism and are tightly integrated into cellular homeostasis. This review provides an update on the latest research concerning the organization and operation of plant mitochondrial redox systems, and how they affect cellular metabolism and signaling, plant development, and stress responses. New insights into the organization and operation of mitochondrial energy systems such as the tricarboxylic acid cycle and mitochondrial electron transport chain (mtETC) are discussed. The mtETC produces reactive oxygen and nitrogen species, which can act as signals or lead to cellular damage, and are thus efficiently removed by mitochondrial antioxidant systems, including Mn-superoxide dismutase, ascorbate–glutathione cycle, and thioredoxin-dependent peroxidases. Plant mitochondria are tightly connected with photosynthesis, photorespiration, and cytosolic metabolism, thereby providing redox-balancing. Mitochondrial proteins are targets of extensive post-translational modifications, but their functional significance and how they are added or removed remains unclear. To operate in sync with the whole cell, mitochondria can communicate their functional status via mitochondrial retrograde signaling to change nuclear gene expression, and several recent breakthroughs here are discussed. At a whole organism level, plant mitochondria thus play crucial roles from the first minutes after seed imbibition, supporting meristem activity, growth, and fertility, until senescence of darkened and aged tissue. Finally, plant mitochondria are tightly integrated with cellular and organismal responses to environmental challenges such as drought, salinity, heat, and submergence, but also threats posed by pathogens. Both the major recent advances and outstanding questions are reviewed, which may help future research efforts on plant mitochondria.

Plant mitochondria are key components of redox homeostasis and play vital roles in regulating cellular metabolism, thereby affecting development and stress tolerance at the whole plant level.

Advances

• Improved quantitative MS-based approaches have accelerated the study of mitochondrial protein abundance, turnover and PTMs.
• Mitochondrial enzymes and cellular compartments operate interactively and efficiently exchange substrates.
• Roles for mitochondrial retrograde signaling in plant growth, during physiologically relevant stress conditions and in interaction with other organelles such as the chloroplasts, have been clarified.
• Further insights into mitochondrial antioxidant and peroxidase systems and how they affect other redox systems, enzymes, and whole plant growth have been generated.
• Our understanding of how mitochondria help plants power development and cope with adversity has improved.

     

Mitophagy: mechanisms, pathophysiological roles, and analysis

Abstract Mitochondria are essential organelles that regulate cellular energy homeostasis and cell death. The removal of damaged mitochondria through autophagy, a process called mitophagy, is thus critical for maintaining proper cellular functions. Indeed, mitophagy has been recently proposed to play critical roles in terminal differentiation of red blood cells, paternal mitochondrial degradation, neurodegenerative diseases, and ischemia or drug-induced tissue injury. Removal of damaged mitochondria through autophagy requires two steps: induction of general autophagy and priming of damaged mitochondria for selective autophagic recognition. Recent progress in mitophagy studies reveals that mitochondrial priming is mediated either by the Pink1-Parkin signaling pathway or the mitophagic receptors Nix and Bnip3. In this review, we summarize our current knowledge on the mechanisms of mitophagy. We also discuss the pathophysiological roles of mitophagy and current assays used to monitor mitophagy.     

Getting to the heart of planar cell polarity signaling

The genes that underpin normal heart development, and which can be disrupted to result in congenital structural malformations, are rapidly being uncovered. However, the specific cellular processes that lie downstream of these genetic cascades, accurately shaping tissues and complex structures within the heart, remain relatively unclear. The noncanonical Wnt planar cell polarity (PCP) signaling pathway is known to have a role in embryonic morphogenesis and as such is an important candidate pathway to carry out these roles in heart development. The pathway regulates the polarization of cells in a variety of contexts, allowing cells to change shape and position and to "know" their orientation within a mass of tissue. PCP signaling has also been shown recently to regulate the cellular position of the primary cilium. This organelle is known to be crucial for the establishment of left-right patterning in the early embryo and may also act as a signaling antenna for other developmental and regulatory pathways. It is not surprising that recent studies have also linked PCP to left-right patterning. In this review, we will examine the current evidence suggesting that PCP signaling has a central role in cardiac development and malformation.     

Mitochondrial retrograde signaling at the crossroads of tumor bioenergetics,genetics and epigenetics

Mitochondria play a central role not only in energy production but also in the integration of metabolic pathways as well as signals for apoptosis and autophagy. It is becoming increasingly apparent that mitochondria in mammalian cells play critical roles in the initiation and propagation of various signaling cascades. In particular, mitochondrial metabolic and respiratory states and status on mitochondrial genetic instability are communicated to the nucleus as an adaptive response through retrograde signaling. Each mammalian cell contains multiple copies of the mitochondrial genome (mtDNA). A reduction in mtDNA copy number has been reported in various human pathological conditions such as diabetes, obesity, neurodegenerative disorders, aging and cancer. Reduction in mtDNA copy number disrupts mitochondrial membrane potential (Δψm) resulting in dysfunctional mitochondria. Dysfunctional mitochondria trigger retrograde signaling and communicate their changing metabolic and functional state to the nucleus as an adaptive response resulting in an altered nuclear gene expression profile and altered cell physiology and morphology. In this review, we provide an overview of the various modes of mitochondrial retrograde signaling focusing particularly on the Ca^2 +/Calcineurin mediated retrograde signaling. We discuss the contribution of the key factors of the pathway such as Calcineurin, IGF1 receptor, Akt kinase and HnRNPA2 in the propagation of signaling and their role in modulating genetic and epigenetic changes favoring cellular reprogramming towards tumorigenesis.     

Signaling in plant embryogenesis

Embryogenesis is a critical stage of the sporophytic life cycle during which the basic body plan of the plant is established. Although positional information is implicated to play a major role in determining embryo cell fate, little is known about the nature of positional signals. Recent studies show that the monopterous and hobbit mutations reveal signaling during patterning of the embryonic axis. The LEAFY COTYLEDON1 and PICKLE genes have been implicated to play important roles in controlling embryo development.     

Retinoic acid affects craniofacial patterning by changing Fgf8 expression in the pharyngeal ectoderm

Retinoic acid signaling plays important roles in establishing normal patterning and cellular differentiation during embryonic development. In this study, we show that single administration of retinoic acid at embryonic day 8.5 causes homeotic transformation of the lower jaw into upper jaw-like structures. This homeosis was preceded by downregulation of Fgf8 and Sprouty expression in the proximal domain of the first pharyngeal arch. Downregulation of mesenchymal genes such as Dlx5, Hand2, Tbx1 and Pitx2 was also observed. The oropharynx in retinoic acid-treated embryos was severely constricted. Consistent with this observation, Patched expression in the arch endoderm and mesenchyme was downregulated. Thus, retinoic acid affects the expression of subsets of epithelial and mesenchymal genes, possibly disrupting the regional identity of the pharyngeal arch.     

Wnt Signaling through the Ror Receptor in the Nervous System

The receptor tyrosine kinase-like orphan receptor (Ror) proteins are conserved tyrosine kinase receptors that play roles in a variety of cellular processes that pattern tissues and organs during vertebrate and invertebrate development. Ror signaling is required for skeleton and neuronal development and modulates cell migration, cell polarity, and convergent extension. Ror has also been implicated in two human skeletal disorders, brachydactyly type B and Robinow syndrome. Rors are widely expressed during metazoan development including domains in the nervous system. Here, we review recent progress in understanding the roles of the Ror receptors in neuronal migration, axonal pruning, axon guidance, and synaptic plasticity. The processes by which Ror signaling execute these diverse roles are still largely unknown, but they likely converge on cytoskeletal remodeling. In multiple species, Rors have been shown to act as Wnt receptors signaling via novel non-canonical Wnt pathways mediated in some tissues by the adapter protein disheveled and the non-receptor tyrosine kinase Src. Rors can either activate or repress Wnt target expression depending on the cellular context and can also modulate signal transduction by sequestering Wnt ligands away from their signaling receptors. Future challenges include the identification of signaling components of the Ror pathways and bettering our understanding of the roles of these pleiotropic receptors in patterning the nervous system.     

MR microscopy of the human fetal upper extremity – a proof-of-principle study

Background

Bone morphogenetic proteins regulate multiple processes in embryonic development, including early dorso-ventral patterning and neural crest development. BMPs activate heteromeric receptor complexes consisting of type I and type II receptor-serine/threonine kinases. BMP receptors Ia and Ib, also known as ALK3 and ALK6 respectively, are the most common type I receptors that likely mediate most BMP signaling events. Since early expression patterns and functions in Xenopus laevis development have not been described, we have addressed these questions in the present study.

Results

Here we have analyzed the temporal and spatial expression patterns of ALK3 and ALK6; we have also carried out loss-of-function studies to define the function of these receptors in early Xenopus development. We detected both redundant and non-redundant roles of ALK3 and ALK6 in dorso-ventral patterning. From late gastrula stages onwards, their expression patterns diverged, which correlated with a specific, non-redundant requirement of ALK6 in post-gastrula neural crest cells. ALK6 was essential for induction of neural crest cell fate and further development of the neural crest and its derivatives.

Conclusions

ALK3 and ALK6 both contribute to the gene regulatory network that regulates dorso-ventral patterning; they play partially overlapping and partially non-redundant roles in this process. ALK3 and ALK6 are independently required for the spatially restricted activation of BMP signaling and msx2 upregulation at the neural plate border, whereas in post-gastrula development ALK6 exerts a highly specific, conserved function in neural crest development.

     

Maternal wnt11 activates the canonical wnt signaling pathway required for axis formation in Xenopus embryos

Wnt signaling pathways play essential roles in patterning and proliferation of embryonic and adult tissues. In many organisms, this signaling pathway directs axis formation. Although the importance of intracellular components of the pathway, including beta-catenin and Tcf3, has been established, the mechanism of their activation is uncertain. In Xenopus, the initiating signal that localizes beta-catenin to dorsal nuclei has been suggested to be intracellular and Wnt independent. Here, we provide three lines of evidence that the pathway specifying the dorsal axis is activated extracellularly in Xenopus embryos. First, we identify Wnt11 as the initiating signal. Second, we show that activation requires the glycosyl transferase X.EXT1. Third, we find that the EGF-CFC protein, FRL1, is also essential and interacts with Wnt11 to activate canonical Wnt signaling.     

Mitochondria and calcium signaling in embryonic development

Calcium (Ca²⁺) is a simple but critical signal for controlling various cellular processes and is especially important in fertilization and embryonic development. The dynamic change of cellular Ca²⁺ concentration and homeostasis are tightly regulated. Cellular Ca²⁺ increases by way of Ca²⁺ influx from extracellular medium and Ca²⁺ release from cellular stores of the endoplasmic reticulum (ER) and sarcoplasmic reticulum (SR). The elevated Ca²⁺ is subsequently sequestered by expelling it out of the cell or by pumping back to the ER/SR. Mitochondria function as a power house for energy production via oxidative phosphorylation in most eukaryotes. In addition to this well-known function, mitochondria are also recognized to regulate Ca²⁺ homeostasis through different mechanisms. Although critical roles of Ca²⁺ signaling in fertilization and embryonic development are known, the involvement of mitochondria in these processes are not fully understood. This review is focused on the role of mitochondrial respiratory chain complex I in the regulation of Ca²⁺ signaling pathway and gene expression in embryonic development, especially on the new findings in the cardiac development of Xenopus embryos. The data demonstrate that mitochondria modulate Ca²⁺ signaling and the Ca²⁺-dependent NFAT pathway and its target gene which are essential for embryonic heart development.     

Distinct developmental programs require different levels of Bmp signaling during mouse retinal development

The Bmp family of secreted signaling molecules is implicated in multiple aspects of embryonic development. However, the cell-type-specific requirements for this signaling pathway are often obscure in the context of complex embryonic tissue interactions. To define the cell-autonomous requirements for Bmp signaling, we have used a Cre-loxP strategy to delete Bmp receptor function specifically within the developing mouse retina. Disruption of a Bmp type I receptor gene, Bmpr1a, leads to no detectable eye abnormality. Further reduction of Bmp receptor activity by removing one functional copy of another Bmp type I receptor gene, Bmpr1b, in the retina-specific Bmpr1a mutant background, results in abnormal retinal dorsoventral patterning. Double mutants completely lacking both of these genes exhibit severe eye defects characterized by reduced growth of embryonic retina and failure of retinal neurogenesis. These studies provide direct genetic evidence that Bmpr1a and Bmpr1b play redundant roles during retinal development, and that different threshold levels of Bmp signaling regulate distinct developmental programs such as patterning, growth and differentiation of the retina.     

The ephrins and Eph receptors in angiogenesis.

Eph receptors are a unique family of receptor tyrosine kinases that play critical roles in embryonic patterning, neuronal targeting, vascular development and adult neovascularization. Engagement of Eph receptors by ephrin ligands mediates critical steps of angiogenesis, including juxtacrine cell-cell contacts, cell adhesion to extracellular matrix, and cell migration. Recent evidence from in vitro angiogenesis assays and analysis of mice deficient for one or more members of the Eph family establishes the role of Eph signaling in sprouting angiogenesis and blood vessel remodeling during vascular development. Furthermore, elevated expression of Eph receptors and ephrin ligands is associated with tumors and associated tumor vasculature, suggesting that Eph receptors and their ephrin ligands also play critical roles in tumor angiogenesis and tumor growth. This review will focus on the relevance of Eph receptor signaling in embryonic and adult neovascularization, and possible contributions to tumor growth and metastasis.     

Sprouty: a common antagonist of FGF and EGF signaling pathways in Drosophila

Extracellular factors such as FGF and EGF control various aspects of morphogenesis, patterning and cellular proliferation in both invertebrates and vertebrates. In most systems, it is primarily the distribution of these factors that controls the differential behavior of the responding cells. Here we describe the role of Sprouty in eye development. Sprouty is an extracellular protein that has been shown to antagonize FGF signaling during tracheal branching in Drosophila. It is a novel type of protein with a highly conserved cysteine-rich region. In addition to the embryonic tracheal system, sprouty is also expressed in other tissues including the developing eye imaginal disc, embryonic chordotonal organ precursors and the midline glia. In each of these tissues, EGF receptor signaling is known to participate in the control of the correct number of neurons or glia. We show that, in all three tissues, the loss of sprouty results in supernumerary neurons or glia, respectively. Furthermore, overexpression of sprouty in wing veins and ovarian follicle cells, two other tissues where EGF signaling is required for patterning, results in phenotypes that resemble the loss-of-function phenotypes of Egf receptor. These results suggest that Sprouty acts as an antagonist of EGF as well as FGF signaling pathways. These receptor tyrosine kinase-mediated pathways may share not only intracellular signaling components but also extracellular factors that modulate the strength of the signal.     

Isolation and Community: A Review of the Role of Gap-Junctional Communication in Embryonic Patterning

Gap junctions are specialized channels formed between the membranes of two adjacent cells. They permit the direct passage of small molecules from the cytosol of one cell to that of its neighbor, and thus form a system of cell-cell communication that exists alongside familiar secretion/receptor signaling. Gap junction states can be regulated at many levels by factors such as membrane voltage, pH, phosphorylation state, and biochemical signals. Because of the rich potential for regulation of junctional conductance, and directional and molecular gating (specificity), gap junctional communication (GJC) plays a crucial role in many aspects of normal tissue physiology, as well as in tumor progression. However, arguably the most exciting role for GJC is in the regulation of information flow that takes place during embryonic development. This review summarizes the current knowledge of how GJC controls various aspects of embryonic morphogenesis in both vertebrate and invertebrate systems. Modern molecular embryology approaches have complemented biophysical and ultrastructural data, and we are beginning to unravel the patterning roles of GJC in embryonic events such as the patterning of the embryonic left-right axis, as well as the morphogenesis of the heart and limb. Proteins from the Connexin (Cx) gene family, as well as innexins and ductin, are now beginning to be understood as the basis for GJC underlying important embryonic patterning events.