Mitochondrial network remodeling: an important feature of myogenesis and skeletal muscle regeneration

The remodeling of the mitochondrial network is a critical process in maintaining cellular homeostasis and is intimately related to mitochondrial function. The interplay between the formation of new mitochondria (biogenesis) and the removal of damaged mitochondria (mitophagy) provide a means for the repopulation of the mitochondrial network. Additionally, mitochondrial fission and fusion serve as a bridge between biogenesis and mitophagy. In recent years, the importance of these processes has been characterised in multiple tissue- and cell-types, and under various conditions. In skeletal muscle, the robust remodeling of the mitochondrial network is observed, particularly after injury where large portions of the tissue/cell structures are damaged. The significance of mitochondrial remodeling in regulating skeletal muscle regeneration has been widely studied, with alterations in mitochondrial remodeling processes leading to incomplete regeneration and impaired skeletal muscle function. Needless to say, important questions related to mitochondrial remodeling and skeletal muscle regeneration still remain unanswered and require further investigation. Therefore, this review will discuss the known molecular mechanisms of mitochondrial network remodeling, as well as integrate these mechanisms and discuss their relevance in myogenesis and regenerating skeletal muscle.

     

Genetics of photoreceptor degeneration and regeneration in zebrafish

Zebrafish are unique in that they provide a useful model system for studying two critically important problems in retinal neurobiology, the mechanisms responsible for triggering photoreceptor cell death and the innate stem cell–mediated regenerative response elicited by this death. In this review we highlight recent seminal findings in these two fields. We first focus on zebrafish as a model for studying photoreceptor degeneration. We summarize the genes currently known to cause photoreceptor degeneration, and we describe the phenotype of a few zebrafish mutants in detail, highlighting the usefulness of this model for studying this process. In the second section, we discuss the several different experimental paradigms that are available to study regeneration in the teleost retina. A model outlining the sequence of gene expression starting from the dedifferentiation of Müller glia to the formation of rod and cone precursors is presented.     

The roles of endogenous retinoid signaling in organ and appendage regeneration

The ability to regenerate injured or lost body parts has been an age-old ambition of medical science. In contrast to humans, teleost fish and urodele amphibians can regrow almost any part of the body with seeming effortlessness. Retinoic acid is a molecule that has long been associated with these impressive regenerative capacities. The discovery 30 years ago that addition of retinoic acid to regenerating amphibian limbs causes “super-regeneration” initiated investigations into the presumptive roles of retinoic acid in regeneration of appendages and other organs. However, the evidence favoring or dismissing a role for endogenous retinoids in regeneration processes remained sparse and ambiguous. Now, the availability of genetic tools to manipulate and visualize the retinoic acid signaling pathway has opened up new routes to dissect its roles in regeneration. Here, we review the current understanding on endogenous functions of retinoic acid in regeneration and discuss key questions to be addressed in future research.     

Non-canonical activation of Notch signaling/target genes in vertebrates

Evolutionarily conserved Notch signaling orchestrates diverse physiological mechanisms during metazoan development and homeostasis. Classically, ligand-activated Notch receptors transduce the signaling cascade through the interaction of DNA-bound CBF1-co-repressor complex. However, recent reports have demonstrated execution of a CBF1-independent Notch pathway through signaling cross-talks in various cells/tissues. Here, we have tried to congregate the reports that describe the non-canonical/CBF1-independent Notch signaling and target gene activation in vertebrates with specific emphasis on their functional relevance.     

Behavioral and neuronal mechanisms of cricket phonotaxis

Summary The auditory communication of crickets provides a model system for the analysis of the neuronal mechanisms underlying complex behavior. The song of male crickets attracts females. The necessary and sufficient parameter of the song for the female phonotaxis has been determined by a quantified behavioral analysis. Neuronal correlates of this pattern recognition exist in the cricket brain and give rise to a hypothesis on the mechanism of song pattern recognition. Causal relationships between the orientation of a cricket during phonotaxis and the activity of single identified neurons were found by monitoring and deactivating single neurons during behavior. The different roles of various identifield neurons for sound localization have been tested by this method. The plasticity of the auditory system at both the behavioral and at the neuronal level has been studied after ampytation of one ear, and a mechanism for sound localization with only one ear is proposed.     

Cell cycle progression by the repression of primary cilia formation in proliferating cells

In most cell types, primary cilia protrude from the cell surface and act as major hubs for cell signaling, cell differentiation, and cell polarity. With the exception of some cells ciliated during cell proliferation, most cells begin to disassemble their primary cilia at cell cycle re-entry. Although the role of primary cilia disassembly on cell cycle progression is still under debate, recent data have emerged to support the idea that primary cilia exert influence on cell cycle progression. In this review, we emphasize a non-mitotic role of Aurora-A not only in the ciliary resorption at cell cycle re-entry but also in continuous suppression of cilia regeneration during cell proliferation. We also summarize recent new findings indicating that forced induction/suppression of primary cilia can affect cell cycle progression, in particular the transition from G0/G1 to S phase. In addition, we speculate how (de)ciliation affects cell cycle progression.     

Molecular mechanisms underlying Th1-like Treg generation and function

Since their ‘re-discovery’ more than two decades ago, FOXP3⁺ regulatory T cells (Tregs) have been an important subject of investigation in the biomedical field and our understanding of the mechanisms that drive their phenotype and function in health and disease has advanced tremendously. During the past few years it has become clear that Tregs are not a terminally differentiated population but show some degree of plasticity, and can, under specific environmental conditions, acquire the phenotype of effector T cells. In particular, recent works have highlighted the acquisition of a Th1-like phenotype by Tregs in several pathological environments. In this review we give an update on the concept of Treg plasticity and the advances in defining the molecular mechanisms that underlie the generation of Th1-like Tregs during an immune response and in different disease settings.     

Insulin-producing cells in the brain of adult Drosophila are regulated by the serotonin 5-HT1A receptor

Insulin signaling regulates lifespan, reproduction, metabolic homeostasis, and resistance to stress in the adult organism. In Drosophila, there are seven insulin-like peptides (DILP1–7). Three of these (DILP2, 3 and 5) are produced in median neurosecretory cells of the brain, designated IPCs. Previous work has suggested that production or release of DILPs in IPCs can be regulated by a factor secreted from the fat body as well as by neuronal GABA or short neuropeptide F. There is also evidence that serotonergic neurons may regulate IPCs. Here, we investigated mechanisms by which serotonin may regulate the IPCs. We show that the IPCs in adult flies express the 5-HT_1A, but not the 5-HT_1B or 5-HT₇ receptors, and that processes of serotonergic neurons impinge on the IPC branches. Knockdown of 5-HT_1A in IPCs by targeted RNA interference (RNAi) leads to increased sensitivity to heat, prolonged recovery after cold knockdown and decreased resistance to starvation. Lipid metabolism is also affected, but no effect on growth was seen. Furthermore, we show that DILP2-immunolevels in IPCs increase after 5-HT_1A knockdown; this is accentuated by starvation. Heterozygous 5-HT_1A mutant flies display the same phenotype in all assays, as seen after targeted 5-HT_1A RNAi, and flies fed the 5-HT_1A antagonist WAY100635 display reduced lifespan at starvation. Our findings suggest that serotonin acts on brain IPCs via the 5-HT_1A receptor, thereby affecting their activity and probably insulin signaling. Thus, we have identified a second inhibitory pathway regulating IPC activity in the Drosophila brain.     

Muscle development, regeneration and laminopathies: how lamins or lamina-associated proteins can contribute to muscle development, regeneration and disease

The aim of this review article is to evaluate the current knowledge on associations between muscle formation and regeneration and components of the nuclear lamina. Lamins and their partners have become particularly intriguing objects of scientific interest since it has been observed that mutations in genes coding for these proteins lead to a wide range of diseases called laminopathies. For over the last 10 years, various laboratories worldwide have tried to explain the pathogenesis of these rare disorders. Analyses of the distinct aspects of laminopathies resulted in formulation of different hypotheses regarding the mechanisms of the development of these diseases. In the light of recent discoveries, A-type lamins—the main building blocks of the nuclear lamina—together with other key elements, such as emerin, LAP2α and nesprins, seem to be of great importance in the modulation of various signaling pathways responsible for cellular differentiation and proliferation.     

Transient receptor potential canonical channels in angiogenesis and axon guidance

Wiring of vascular and neural networks requires precise guidance of growing blood vessels and axons, respectively, to reach their targets during development. Both of the processes share common molecular signaling pathways. Transient receptor potential canonical (TRPC) channels are calcium-permeable cation channels and gated via receptor- or store-operated mechanisms. Recent studies have revealed the requirement of TRPC channels in mediating guidance cue-induced calcium influx and their essential roles in regulating axon navigation and angiogenesis. Dissecting TRPC functions in these physiological processes may provide therapeutic implications for suppressing pathological angiogenesis and improving nerve regeneration.     

PCSK9 regulates neuronal apoptosis by adjusting ApoER2 levels and signaling

The secreted protease proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low-density lipid (LDL) receptor family members LDLR, very low density lipoprotein receptor (VLDLR) and apolipoprotein receptor 2 (ApoER2), and promotes their degradation in intracellular acidic compartments. In the liver, LDLR is a major controller of blood LDL levels, whereas VLDLR and ApoER2 in the brain mediate Reelin signaling, a critical pathway for proper development of the nervous system. Expression level of PCSK9 in the brain is highest in the cerebellum during perinatal development, but is also increased in the adult brain after ischemia. The mechanism of PCSK9 function and its involvement in neuronal apoptosis is poorly understood. We show here that RNAi-mediated knockdown of PCSK9 significantly reduced the death of potassium-deprived cerebellar granule neurons (CGN), as shown by reduced levels of nuclear phosphorylated c-Jun and activated caspase-3, as well as condensed apoptotic nuclei. ApoER2 protein levels were increased in PCSK9 RNAi cells. Knockdown of ApoER2 but not of VLDLR was sufficient to reverse the protection provided by PCSK9 RNAi, suggesting that proapoptotic signaling of PCSK9 is mediated by altered ApoER2 function. Pharmacological inhibition of signaling pathways associated with lipoprotein receptors suggested that PCSK9 regulates neuronal apoptosis independently of NMDA receptor function but in concert with ERK and JNK signaling pathways. PCSK9 RNAi also reduced staurosporine-induced CGN apoptosis and axonal degeneration in the nerve growth factor-deprived dorsal root ganglion neurons. We conclude that PCSK9 potentiates neuronal apoptosis via modulation of ApoER2 levels and related anti-apoptotic signaling pathways.     

Hh signaling in regeneration of the ischemic heart

Myocardial infarction (MI) is caused by the occlusion of a coronary artery due to underlying atherosclerosis complicated by localized thrombosis. The blockage of blood flow leads to cardiomyocyte (CM) death in the infarcted area. Adult mammalian cardiomyocytes have little capacity to proliferate in response to injury; however, some pathways active during embryogenesis and silent during adult life are recruited in response to tissue injury. One such example is hedgehog (Hh) signaling. Hh is involved in the embryonic development of the heart and coronary vascular system. Pathological conditions including ischemia activate Hh signaling in adult tissues. This review highlights the involvement of Hh signaling in ischemic tissue regeneration with a particular emphasis on heart regeneration and discusses its potential role as a therapeutic agent.     

Signaling pathways and the cerebral cavernous malformations proteins: lessons from structural biology

Cerebral cavernous malformations (CCM) are neurovascular dysplasias that result in mulberry-shaped lesions predominantly located in brain and spinal tissues. Mutations in three genes are associated with CCM. These genes encode for the proteins KRIT1/CCM1 (krev interaction trapped 1/cerebral cavernous malformations 1), cerebral cavernous malformations 2, osmosensing scaffold for MEKK3 (CCM2/malcavernin/OSM), and cerebral cavernous malformations 3/programmed cell death 10 (CCM3/PDCD10). There have been many significant recent advances in our understanding of the structure and function of these proteins, as well as in their roles in cellular signaling. Here, we provide an update on the current knowledge of the structure of the CCM proteins and their functions within cellular signaling, particularly in cellular adhesion complexes and signaling cascades. We go on to discuss subcellular localization of the CCM proteins, the formation and regulation of the CCM complex signaling platform, and current progress towards targeted therapy for CCM disease. Recent structural studies have begun to shed new light on CCM protein function, and we focus here on how these studies have helped inform the current understanding of these roles and how they may aid future studies into both CCM-related biology and disease mechanisms.     

Carbonic anhydrase type II in regenerating retinal pigment epithelium. A histochemical study in the rabbit

Type II carbonic anhydrase (CAII) in the cytoplasm of the retinal pigment epithelium (RPE) may contribute to the transport of water and solutes across the RPE. The activity of this enzyme in RPE during its response to damage, e.g., during regeneration, is therefore of interest in understanding retinal disease. Immuno-histochemistry was used to compare CAII activity of normal RPE and RPE experimentally induced to regenerate. In normal rabbits, the RPE stained intensely with a peroxidase-linked antibody specific for human CAII. Regenerating RPE stained less intensely. Within the regenerating epithelium, staining appeared more intense in mature cells than in immature ones, suggesting that CAII activity gradually returns during RPE regeneration.     

The buzz on caffeine in invertebrates: effects on behavior and molecular mechanisms

A number of recent studies from as diverse fields as plant–pollinator interactions, analyses of caffeine as an environmental pollutant, and the ability of caffeine to provide protection against neurodegenerative diseases have generated interest in understanding the actions of caffeine in invertebrates. This review summarizes what is currently known about the effects of caffeine on behavior and its molecular mechanisms in invertebrates. Caffeine appears to have similar effects on locomotion and sleep in both invertebrates and mammals. Furthermore, as in mammals, caffeine appears to have complex effects on learning and memory. However, the underlying mechanisms for these effects may differ between invertebrates and vertebrates. While caffeine’s ability to cause release of intracellular calcium stores via ryanodine receptors and its actions as a phosphodiesterase inhibitor have been clearly established in invertebrates, its ability to interact with invertebrate adenosine receptors remains an important open question. Initial studies in insects and mollusks suggest an interaction between caffeine and the dopamine signaling pathway; more work needs to be done to understand the mechanisms by which caffeine influences signaling via biogenic amines. As of yet, little is known about whether other actions of caffeine in vertebrates, such as its effects on GABA_A and glycine receptors, are conserved. Furthermore, the pharmacokinetics of caffeine remains to be elucidated. Overall behavioral responses to caffeine appear to be conserved amongst organisms; however, we are just beginning to understand the mechanisms underlying its effects across animal phyla.     

The role of estrogen receptor α in the regulation of bone and growth plate cartilage

Estrogens are important endocrine regulators of skeletal growth and maintenance in both females and males. Studies have demonstrated that the estrogen receptor (ER)-α is the main mediator of these estrogenic effects in bone. Therefore, estrogen signaling via ERα is a target both for affecting longitudinal bone growth and bone remodeling. However, treatment with estradiol (E2) leads to an increased risk of side effects such as venous thromboembolism and breast cancer. Thus, an improved understanding of the signaling pathways of ERα will be essential in order to find better bone specific treatments with minimal adverse effects for different estrogen-related bone disorders. This review summarizes the recent data regarding the intracellular signaling mechanisms, in vivo, mediated by the ERα activation functions (AFs), AF-1 and AF-2, and the effect on bone, growth plate and other estrogen responsive tissues. In addition, we review the recent cell-specific ERα-deleted mouse models lacking ERα specifically in neuronal cells or growth plate cartilage. The newly characterized signaling pathways of estrogen, described in this review, provide a better understanding of the ERα signaling pathways, which may facilitate the design of new, bone-specific treatment strategies with minimal adverse effects.     

Molecular and structural effects of inverse agonistic mutations on signaling of the thyrotropin receptor – a basally active GPCR

Several mutations that decrease the basal signaling activity of G-protein coupled receptors (GPCRs) with pathogenic implications are known. Here we study the molecular mechanisms responsible for this phenotype and investigate how basal and further activated receptor conformations are interrelated. In the basally active thyroid stimulating hormone receptor (TSHR) we combined spatially-distant mutations with opposing effects on basal activity in double-mutations and characterized mutant basal and TSH induced signaling. Mutations lowering basal activity always have a suppressive influence on TSH induced signaling and on constitutively activating mutations (CAMs). Our results suggest that the conformation of a basally ‘silenced’ GPCR might impair its intrinsic capacity for signaling compared to the wild-type. Striking differences in conformation and intramolecular interactions between TSHR models built using the crystal structures of inactive rhodopsin and partially active opsin help illuminate the molecular details underlying mutations decreasing basal activity. G. Kleinau, H. Jaeschke: These two authors contributed equally to this work. Received 31 July 2008; received after revision 12 September 2008; accepted 19 September 2008     

Ruminations on dietary restriction and aging

Calorie restriction has been known for many decades to extend the life span of rodents. Since the more recent discovery that a long-term reduction in nutrient intake also extends life span in nearly every invertebrate model organism used for aging research, the mechanisms behind the longevity benefits of this intervention have been under intense scrutiny. While models have been developed in yeast, worms, and flies, the molecular mechanisms governing life span extension by calorie restriction remain controversial, resulting in great anticipation of mammalian studies testing these models. Here we discuss the links between nutrient reduction and enhanced longevity with emphasis on evolutionarily conserved nutrient response signaling. Received 1 November 2006; received after revision 15 December 2006; accepted 27 February 2007     

Notch and cancer: a double-edged sword

The highly conserved Notch signaling pathway plays pleiotropic roles during embryonic development and is important for the regulation of selfrenewing tissues. The physiological functions of this signaling cascade range from stem cell maintenance and influencing cell fate decisions of barely differentiated progenitor cells, to the induction of terminal differentiation processes, all of which have been found to be recapitulated in different forms of cancers. Although Notch signaling has mostly been associated with oncogenic and growth-promoting roles, depending on the tissue type it can also function as a tumor suppressor. Here we describe recent findings on Notch signaling in cancer and tumor angiogenesis, and highlight some of the therapeutic approaches that are currently being developed to interfere with tumor growth and progression. Received 2 April 2007; received after revision 29 June 2007; accepted 2 July 2007