Fibroblast growth factors as regulators of central nervous system development and function

Fibroblast growth factors (FGFs) are multifunctional signaling proteins that regulate developmental processes and adult physiology. Over the last few years, important progress has been made in understanding the function of FGFs in the embryonic and adult central nervous system. In this review, I will first discuss studies showing that FGF signaling is already required during formation of the neural plate. Next, I will describe how FGF signaling centers control growth and patterning of specific brain structures. Finally, I will focus on the function of FGF signaling in the adult brain and in regulating maintenance and repair of damaged neural tissues.     

The GID ubiquitin ligase complex is a regulator of AMPK activity and organismal lifespan

ABSTRACT

The AMP-activated protein kinase (AMPK) regulates cellular energy homeostasis by sensing the metabolic status of the cell. AMPK is regulated by phosphorylation and dephosphorylation as a result of changing AMP/ATP levels and by removal of inhibitory ubiquitin residues by USP10. In this context, we identified the GID-complex, an evolutionarily conserved ubiquitin-ligase-complex (E3), as a negative regulator of AMPK activity. Our data show that the GID-complex targets AMPK for ubiquitination thereby altering its activity. Cells depleted of GID-subunits mimic a state of starvation as shown by increased AMPK activity and macroautophagic/autophagic flux as well as reduced MTOR activation. Consistently, gid-genes knockdown in C. elegans results in increased organismal lifespan. This study may contribute to understand metabolic disorders such as type 2 diabetes mellitus and morbid obesity and implements alternative therapeutic approaches to alter AMPK activity.     

Tyrosine phosphatases as regulators of skeletal development and metabolism

The protein tyrosine kinases (PTK) and the protein tyrosine phosphatases (PTPs) are enzymes which play an integral role in tyrosine phosphorylation-dependent signaling cascades. By catalyzing the phosphorylation and dephosphorylation of cellular proteins, these enzymes direct the steady-state levels of specific phosphoproteins and ultimately dictate the functional state of all cells. The importance of this type of signaling in the skeleton is accepted but poorly understood. The contribution of the PTKs to signaling events in bone has been well studied but, in contrast, the regulation by PTPs is poorly defined. The recent identification of 107 genes within the human genome which encode members of the PTP superfamily emphasizes the need to consider the importance of these proteins in skeletal tissue. In this prospective, we will summarize the present state of our knowledge regarding the function of this enzyme superfamily, illustrating its relevance to the development and maintenance of the skeleton and highlighting future directions that should improve our understanding of these critical signaling molecules.     

Schwann cells as regulators of nerve development.

Myelinating and non-myelinating Schwann cells of peripheral nerves are derived from the neural crest via an intermediate cell type, the Schwann cell precursor [K.R. Jessen, A. Brennan, L. Morgan, R. Mirsky, A. Kent, Y. Hashimoto, J. Gavrilovic. The Schwann cell precursor and its fate: a study of cell death and differentiation during gliogenesis in rat embryonic nerves, Neuron 12 (1994) 509-527]. The survival and maturation of Schwann cell precursors is controlled by a neuronally derived signal, beta neuregulin. Other factors, in particular endothelins, regulate the timing of precursor maturation and Schwann cell generation. In turn, signals derived from Schwann cell precursors or Schwann cells regulate neuronal numbers during development, and axonal calibre, distribution of ion channels and neurofilament phosphorylation in myelinated axons. Unlike Schwann cell precursors, Schwann cells in older nerves survive in the absence of axons, indicating that a significant change in survival regulation occurs. This is due primarily to the presence of autocrine growth factor loops in Schwann cells, present from embryo day 18 onwards, that are not functional in Schwann cell precursors. The most important components of the autocrine loop are insulin-like growth factors, platelet derived growth factor-BB and neurotrophin 3, which together with laminin support long-term Schwann cell survival. The paracrine dependence of precursors on axons for survival provides a mechanism for matching precursor cell number to axons in embryonic nerves, while the ability of Schwann cells to survive in the absence of axons is an absolute prerequisite for nerve repair following injury. In addition to providing survival factors to neurones and themselves, and signals that determine axonal architecture, Schwann cells also control the formation of peripheral nerve sheaths. This involves Schwann cell-derived Desert Hedgehog, which directs the transition of mesenchymal cells to form the epithelium-like structure of the perineurium. Schwann cells thus signal not only to themselves but also to the other cellular components within the nerve to act as major regulators of nerve development.     

Thrombospondins as key regulators of synaptogenesis in the central nervous system

Thrombospondins (TSPs) are a family of large, oligomeric multidomain glycoproteins that participate in a variety of biological functions as part of the extracellular matrix (ECM). Through their associations with a number of binding partners, TSPs mediate complex cell-cell and cell-matrix interactions in such diverse processes as angiogenesis, inflammation, osteogenesis, cell proliferation, and apoptosis. It was recently shown in the developing central nervous system (CNS) that TSPs promote the formation of new synapses, which are the unique cell-cell adhesions between neurons in the brain. This increase in synaptogenesis is mediated by the interaction between astrocyte-secreted TSPs and their neuronal receptor, calcium channel subunit α2δ-1. The cellular and molecular mechanisms that underlie induction of synaptogenesis via this interaction are yet to be fully elucidated. This review will focus on what is known about TSP and synapse formation during development, possible roles for TSP following brain injury, and what the previously established actions of TSP in other biological tissues may tell us about the mechanisms underlying TSP's functions in CNS synaptogenesis.     

Active participation of cell death in development and organismal homeostasis

The precise, regional execution of programmed cell death is required for the proper patterning and sculpting of the embryonic primordium during animal development. In addition, cell death that is not directly involved in sculpting is also widely observed. The most abundant morphological form of programmed cell death in developing animals is apoptosis, and identification of the apoptotic genetic pathways has enabled the study of apoptosis' regulation and roles during development. Genetic and bio-imaging studies have permitted the study of the active roles of cell death in development and organismal homeostasis.     

TRAF proteins as key regulators of plant development and stress responses

Tumor necrosis factor receptor-associated factor (TRAF) proteins are conserved in higher eukaryotes and play key roles in transducing cellular signals across different organelles. They are characterized by their C-terminal region (TRAF-C domain) containing seven to eight anti-parallel β-sheets, also known as the meprin and TRAF-C homology (MATH) domain. Over the past few decades, significant progress has been made toward understanding the diverse roles of TRAF proteins in mammals and plants. Compared to other eukaryotic species, the Arabidopsis thaliana and rice (Oryza sativa) genomes encode many more TRAF/MATH domain-containing proteins; these plant proteins cluster into five classes: TRAF/MATH-only, MATH-BPM, MATH-UBP (ubiquitin protease), Seven in absentia (SINA), and MATH-Filament and MATH-PEARLI-4 proteins, suggesting parallel evolution of TRAF proteins in plants. Increasing evidence now indicates that plant TRAF proteins form central signaling networks essential for multiple biological processes, such as vegetative and reproductive development, autophagosome formation, plant immunity, symbiosis, phytohormone signaling, and abiotic stress responses. Here, we summarize recent advances and highlight future prospects for understanding on the molecular mechanisms by which TRAF proteins act in plant development and stress responses.     

Oligodendrocytes as regulators of neuronal networks during early postnatal development

Oligodendrocytes are the glial cells responsible for myelin formation. Myelination occurs during the first postnatal weeks and, in rodents, is completed during the third week after birth. Myelin ensures the fast conduction of the nerve impulse; in the adult, myelin proteins have an inhibitory role on axon growth and regeneration after injury. During brain development, oligodendrocytes precursors originating in multiple locations along the antero-posterior axis actively proliferate and migrate to colonize the whole brain. Whether the initial interactions between oligodendrocytes and neurons might play a functional role before the onset of myelination is still not completely elucidated. In this article, we addressed this question by transgenically targeted ablation of proliferating oligodendrocytes during cerebellum development. Interestingly, we show that depletion of oligodendrocytes at postnatal day 1 (P1) profoundly affects the establishment of cerebellar circuitries. We observed an impressive deregulation in the expression of molecules involved in axon growth, guidance and synaptic plasticity. These effects were accompanied by an outstanding increase of neurofilament staining observed 4 hours after the beginning of the ablation protocol, likely dependent from sprouting of cerebellar fibers. Oligodendrocyte ablation modifies localization and function of ionotropic glutamate receptors in Purkinje neurons. These results show a novel oligodendrocyte function expressed during early postnatal brain development, where these cells participate in the formation of cerebellar circuitries, and influence its development.     

Novel light-activated protein kinases as key regulators of plant growth and development

Plants have evolved highly sensitive sensory photoreceptor systems to regulate various aspects of their growth and development. Many responses such as seed germination, flowering and dormancy are controlled by red and far-red regions of the solar spectrum through the phytochrome family of photoreceptors. However, several other responses such as stem growth inhibition, phototropism and opening of stomata are controlled by blue and/or ultraviolet light absorbing photoreceptors called cryptochromes and phototropin. Despite their central role in plant biology, the mode of action of these photoreceptors has been shrouded in mystery. Even the biochemical isolation of a photoreceptor, as in the case of phytochrome was accomplished decades ago, did not help in elucidating the mechanism of action. Nevertheless, due to advances in recombinant DNA technology, generation of extensive databanks and the capability to predict function by base sequence analysis, a breakthrough has now come about. It is clear that certain phytochromes, at least in the cyanobacteria and algae which represent the simplest plants, are hybrid photoreceptor-cum-kinases. These novel kinases utilize captured photons rather than conventional ligands to trigger conformational change and in consequence enzyme activity. The kinases apparently, then, cause phosphorylation of many other types of target molecules, leading eventually to various developmental changes. There is suggestive evidence that in higher plants, too, at least some phytochromes may operate as kinases. As compared to work on phytochromes, the blue light photoreceptors have begun to be studied only recently. However, the exciting discovery has been made of at least one photoactive kinase that is critically required for phototropism. This article summarizes the above discoveries from the perspective of general biology. Dedicated to the memory of Drs Harry Borthwick, Sterling Hendricks and James Bonner whose classical studies paved the way for modern researches on mechanism of action of plant photoreceptors and whom the senior author was previleged to know.     

Methylation of polyphenols with vicinal hydroxyl groups: A protection pathway increasing organismal lifespan

Comment on: Kunstmann B, et al. Aging 2009; 1:328-334.     

Limbiting outgrowth: BMPs as negative regulators in limb development

Rapid progress is being made in understanding how integrated signaling pathways direct patterned outgrowth of the vertebrate limb. In contrast, the mechanisms that constrain limb outgrowth, and thus delimit adult morphology, remain poorly understood. Two recent pioneering reports have implicated bone morphogenetic proteins (BMPs) in negatively regulating the function of the apical ectodermal ridge (AER), an inductive structure required for continued proximodistal specification of limb elements.^(1,2) These studies provide the first insights into how the termination of a limb bud signaling center is accomplished, and intriguingly suggest how distinct aspects of limb morphogenesis are regulated. BioEssays 21:721–725, 1999. © 1999 John Wiley & Sons, Inc.     

Mitochondria as biological targets for stem cell and organismal senescence

Organismal aging is impacted by the deterioration of tissue turnover mechanisms due, in part, to the decline in stem cell function. This decline can be related to mitochondrial dysfunction and underlying energetic defects that, in concert, help drive biological aging. Thus, mitochondria have been described as a potential interventional target to hinder the loss of stem cell robustness, and subsequently, decrease tissue turnover decline and age-associated pathologies. In this review, we focused our analysis on the most recent literature on mitochondria and stem cell aging and discuss the potential benefits of targeting mitochondria in preventing stem cell dysfunction and thus influencing aging.     

Word learning and lexical development across the lifespan

Word learning is one of the core components of language acquisition. In this article, we provide an overview of the theme issue on word learning, describing some of the ways in which research in the area has progressed and diverged. In recent years, word learning has become central in a wider range of research areas, and is important to research on adult, as well as child and infant language. We introduce 10 papers that cover the recent developments from a wide range of perspectives, focusing on developmental research, the influence of reading skills, neuroimaging and the relationship between word learning and general models of memory.