The programmed cell death that occurs as part of normal mammalian development was first observed nearly a century ago (Collin 1906). It has since been established that approximately half of all neurons in the neuroaxis and >99.9% of the total number of cells generated during the course of a human lifetime go on to die through a process of apoptosis (for review, see Datta and Greenberg 1998; Vaux and Korsmeyer 1999). The induction of developmental cell death is a highly regulated process and can be suppressed by a variety of extracellular stimuli. The purification in the 1950s of the nerve growth factor (NGF), which promotes the survival of sympathetic neurons, set the stage for the discovery that peptide trophic factors promote the survival of a wide variety of cell types in vitro and in vivo (Levi-Montalcini 1987). The profound biological consequences of growth factor (GF) suppression of apoptosis are exemplified by the critical role of target-derived neurotrophins in the survival of neurons and the maintenance of functional neuronal circuits. (Pettmann and Henderson 1998). Recently, the ability of trophic factors to promote survival have been attributed, at least in part, to the phosphatidylinositide 38-OH kinase (PI3K)/c-Akt kinase cascade. Several targets of the PI3K/c-Akt signaling pathway have been recently identified that may underlie the ability of this regulatory cascade to promote survival. These substrates include two components of the intrinsic cell death machinery, BAD and caspase 9, transcription factors of the forkhead family, and a kinase, IKK, that regulates the NF-kB transcription factor. This article reviews the mechanisms by which survival factors regulate the PI3K/c-Akt cascade, the evidence that activation of the PI3K/c-Akt pathway promotes cell survival, and the current spectrum of c-Akt targets and their roles in mediating c-Akt-dependent cell survival.

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Cellular survival: a play in three Akts

A central question in cell biology is how membrane-spanning receptors transmit extracellular signals inside cells to modulate cell adhesion and motility. Focal adhesion kinase (FAK) is a crucial signalling component that is activated by numerous stimuli and functions as a biosensor or integrator to control cell motility. Through multifaceted and diverse molecular connections, FAK can influence the cytoskeleton, structures of cell adhesion sites and membrane protrusions to regulate cell movement.

Focal adhesion kinase: in command and control of cell motility

The ability to respond to perturbations in endoplasmic reticulum (ER) function is a fundamentally important property of all cells, but ER stress can also lead to apoptosis. In settings of chronic ER stress, the associated apoptosis may contribute to pathophysiological processes involved in a number of prevalent diseases, including neurodegenerative diseases, diabetes, atherosclerosis and renal disease. The molecular mechanisms linking ER stress to apoptosis are the topic of this review, with emphases on relevance to pathophysiology and integration and complementation among the various apoptotic pathways induced by ER stress.

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Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress.

The neurotrophins are a family of proteins that are essential for the development of the vertebrate nervous system. Each neurotrophin can signal through two different types of cell surface receptor — the Trk receptor tyrosine kinases and the p75 neurotrophin receptor. Given the wide range of activities that are now associated with neurotrophins, it is probable that additional regulatory events and signalling systems are involved. Here, I review recent findings that neurotrophins, in addition to promoting survival and differentiation, exert various effects through surprising interactions with other receptors and ion channels.

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Neurotrophins and their receptors: a convergence point for many signalling pathways.

Glycogen synthase kinase 3 (GSK-3) is a multifunctional serine/threonine kinase found in all eukaryotes. The enzyme is a key regulator of numerous signalling pathways, including cellular responses to Wnt, receptor tyrosine kinases and G-protein-coupled receptors and is involved in a wide range of cellular processes, ranging from glycogen metabolism to cell cycle regulation and proliferation. GSK-3 is unusual in that it is normally active in cells and is primarily regulated through inhibition of its activity. Another peculiarity compared with other protein kinases is its preference for primed substrates, that is, substrates previously phosphorylated by another kinase. Several recent advances have improved our understanding of GSK-3 regulation in multiple pathways. These include the solution of the crystal structure of GSK-3, which has provided insight into GSK-3's penchant for primed substrates and the regulation of GSK-3 by serine phosphorylation, and findings related to the involvement of GSK-3 in the Wnt/beta-catenin and Hedgehog pathways. Finally, since increased GSK-3 activity may be linked to pathology in diseases such as Alzheimer's disease and non-insulin-dependent diabetes mellitus, several new GSK-3 inhibitors, such as the aloisines, the paullones and the maleimides, have been developed. Although they are just starting to be characterized in cell culture experiments, these new inhibitors hold promise as therapeutic agents.

GSK-3: tricks of the trade for a multi-tasking kinase.

Maintenance of GABAergic Activity by Neuregulin 1-ErbB4 in Amygdala for Fear Memory

Osteocytes, derived from osteoblast (OB)-lineage, occupy lacunae within bone matrix and exhibit unique morphology with dendrite-like projections to form an inter-connected network. Such a network is essential for osteocytes to monitor and orchestrate bone homeostasis. Thus, it is of considerable interest to investigate how osteocytes are formed and how they built the network. Here we provide evidence for ATP6AP2, an accessory subunit of V-ATPase, in OB-lineage cells to be critical for OB-to-osteocyte transition, and osteocyte distribution, maturation, and morphogenesis. Mice (ATP6AP2Ocn-Cre) that selectively deplete ATP6AP2 in OB-lineage cells results in altered osteocyte distribution and morphology, impaired osteocyte maturation and dendrite-like processes, increased osteocyte cell death and cortical woven bone formation. Further mechanistic studies identify MMP14 (matrix metalloproteinase-14) as a critical downstream of ATP6AP2 for osteocyte differentiation. ATP6AP2 interacts with MMP14 and promotes MMP14 surface distribution largely in immature- or osteoid-osteocytes, where this pathway regulates bone matrix remodeling and osteocyte differentiation. Expression of MMP14 into ATP6AP2 knock out OB-lineage cells in the mouse cortical bone could diminish the deficits in osteocyte maturation, dendrite-like process formation, and survival. These results thus demonstrate an un-recognized function of ATP6AP2 in promoting OB-to-osteocyte transition and uncover a pathway from ATP6AP2-to-MMP14 in osteocyte differentiation.

ATP6AP2-to-MMP14, a key pathway for osteoblast to osteocyte transition

Dorsal Dentate Gyrus, a Key Regulator for Mood and Psychiatric Disorders

Corrigendum: Erbin interacts with TARP γ-2 for surface expression of AMPA receptors in cortical interneurons

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Wen Cheng Xiong

Papers

Maintenance of GABAergic Activity by Neuregulin 1-ErbB4 in Amygdala for Fear Memory

ATP6AP2-to-MMP14, a key pathway for osteoblast to osteocyte transition

Dorsal Dentate Gyrus, a Key Regulator for Mood and Psychiatric Disorders

Corrigendum: Erbin interacts with TARP γ-2 for surface expression of AMPA receptors in cortical interneurons