DNA damage-induced cell death： lessons from the central nervous system

DNA damage can, but does not always, induce cell death. While several pathways linking DNA damage signals to mitochondria-dependent and -independent death machineries have been elucidated, the connectivity of these pathways is subject to regulation by multiple other factors that are not well understood. We have proposed two conceptual models to explain the delayed and variable cell death response to DNA damage： integrative surveillance versus autonomous pathways. In this review, we discuss how these two models may explain the in vivo regulation of cell death induced by ionizing radiation （IR） in the developing central nervous system, where the death response is regulated by radiation dose, cell cycle status and neuronal development.     

Receptors for insulin-like growth factors in the central nervous system: structure and function

Insulin-like growth factors (IGFs) I and II are homologous peptides, which stimulate growth of several vertebrate tissues. Expression of IGF I and IGF II genes and production of IGFs have recently been demonstrated in rat and human brain. In search for the function of IGF I and IGF II in the central nervous system, we have studied IGF receptors in fetal and adult mammalian brain and growth effects of IGFs on primary cultures of fetal rat astrocytes. Two types of IGF receptor are present on adult rat brain cortical plasma membranes, on fetal rat astrocytes and on human glioma cells. Type I IGF receptor is composed of 2 types of subunits: alpha-subunits which bind IGF I and IGF II with high affinity and insulin weakly, and beta-subunits which show tyrosine kinase activity and autophosphorylation stimulated by IGF I and IGF II with almost similar potency. The molecular size of the type I IGF receptor alpha-subunit is larger in cultured fetal rat astrocytes and human glioma cells than in normal adult brain (Mr 130,000 versus 115,000), whereas the beta-subunit has the same electrophoretic mobility (Mr 94,000). The type II IGF receptor is a monomeric protein (Mr 250,000), which binds IGF II 5 times better than IGF I, and does not recognize insulin. The amounts of type II IGF receptor are significantly higher in fetal and malignant cells than in adult brain. Based on these findings we suggest that IGF receptors in brain undergo changes during fetal development and malignant transformation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cell death in the nervous system

Programmed cell death is an essential process for proper neural development. Cell death, with its similar regulatory and executory mechanisms, also contributes to the origin or progression of many or even all neurodegenerative diseases. An understanding of the mechanisms that regulate cell death during neural development may provide new targets and tools to prevent neurodegeneration. Many studies that have focused mainly on insulin-like growth factor-I (IGF-I), have shown that insulin-related growth factors are widely expressed in the developing and adult nervous system, and positively modulate a number of processes during neural development, as well as in adult neuronal and glial physiology. These factors also show neuroprotective effects following neural damage. Although some specific actions have been demonstrated to be anti-apoptotic, we propose that a broad neuroprotective role is the foundation for many of the observed functions of the insulin-related growth factors, whose therapeutical potential for nervous system disorders may be greater than currently accepted.     

The role of the insulin-like growth factors in the central nervous system

Increasing evidence strongly supports a role for insulin-like growth factor-I (IGF-I) in central nervous system (CNS) development. IGF-I, IGF-II, the type IIGF receptor (the cell surface tyrosine kinase receptor that mediates IGF signals), and some IGF binding proteins (IGFBPs; secreted proteins that modulate IGF actions) are expressed in many regions of the CNS beginningin utero. The expression pattern of IGF system proteins during brain growth suggests highly regulated and developmentally timed IGF actions on specific neural cell populations. IGF-I expression is predominantly in neurons and, in many brain regions, peaks in a fashion temporally coincident with periods in development when neuron progenitor proliferation and/or neuritic outgrowth occurs. In contrast, IGF-II expression is confined mainly to cells of mesenchymal and neural crest origin. While expression of type I IGF receptors appears ubiquitous, that of IGFBPs is characterized by regional and developmental specificity, and often occurs coordinately with peaks of IGF expression. In vitro IGF-I has been shown to stimulate the proliferation of neuron progenitors and/or the survival of neurons and oligodendrocytes, and in some cultured neurons, to stimulate function. Transgenic (Tg) mice that overexpress IGF-I in the brain exhibit postnatal brain overgrowth without anatomic abnormality (20–85% increases in weight, depending on the magnitude of expression). In contrast, Tg mice that exhibit ectopic brain expression of IGFBP-1, an inhibitor of IGF action when present in molar excess, manifest postnatal brain growth retardation, and mice with ablated IGF-I gene expression, accomplished by homologous recombination, have brains that are 60% of normal size as adults. Taken together, these in vivo studies indicate that IGF-I can influence the development of most, if not all, brain regions, and suggest that the cerebral cortex and cerebellum are especially sensitive to IGF-I actions. IGF-I’s growth-promoting in vivo actions result from its capacity to increase neuron number, at least in certain populations, and from its potent stimulation of myelination. These IGF-I actions, taken together with its neuroprotective effects following CNS and peripheral nerve injury, suggest that it may be of therapeutic benefit in a wide variety of disorders affecting the nervous system.     

Cell death and the developing enteric nervous system

This review discusses current knowledge about cell death in the developing enteric nervous system (ENS). It also includes findings about the molecular mechanisms by which such death is mediated. Additional consideration is given to trophic factors that contribute to survival of the precursors and neurons and glia of the ENS, as well to genes that, when mutated or deleted, trigger their death. Although further confirmation is needed, present observations support the view that enteric neural crest-derived precursor cells en route to the gut undergo substantial levels of apoptotic death, but that once these cells colonize the gut, there is relatively little death of precursor cells or of neurons and glia during the fetal period. There are also indications that normal neuron loss occurs in the ENS, but at times beyond the perinatal stage. Taken together, these findings suggest that ENS development is similar is some ways, but different in others from extra-enteric areas of the vertebrate central and peripheral nervous systems, in which large-scale apoptotic death of precursor neurons and glia occurs during the fetal and perinatal periods. Potential reasons for these differences are discussed such as a fetal enteric microenvironment that is especially rich in trophic support. In addition to the cell death that occurs during normal ENS development, this review discusses mechanisms of experimentally-induced ENS cell death, such as those that are associated with defective glial cell-line derived neurotrophic factor/Ret signaling, which are an animal model of human congenital megacolon (aganglionosis; Hirschsprung’s disease). Such considerations underscore the importance of understanding cell death in the developing ENS, not just from a curiosity-driven point of view, but also because the pathophysiology behind many disorders of human gastrointestinal function may originate in abnormalities of the mechanisms that govern cell survival and death during ENS development.     

Insulin and insulin-like growth factor receptors in the nervous system

Insulin and the insulin-like growth factors (I and II) are homologous peptides essential to normal metabolism as well as growth. These peptide hormones are present in the brain, and, based on biosynthetic labeling studies as well as evidence for local gene expression, they are synthesized by nervous tissue as well as being taken up by the brain from the peripheral circulation. Furthermore, the presence of insulin and IGF receptors in the brain, on both neuronal and glial cells, also suggests a role for these peptides in the nervous system. Thus, these ligands affect brain electrical activity, either as neurotransmitters or as neuromodulators, altering the release and re-uptake of other neurotransmitters. The insulin and IGF-I and -II receptors found in the brain exhibit a lower molecular weight than corresponding receptors on peripheral tissues, primarily caused by alterations in glycosylation. Despite these alterations, both brain insulin and IGF-I receptors exhibit tyrosine kinase activity in cell-free systems, as do their peripheral counterparts. Brain insulin and IGF-I receptors are developmentally regulated, with the highest levels appearing in fetal or perinatal life. However, the altered glycosylation of brain receptors does not appear until late in fetal development. The receptors are widely distributed in the brain, but especially enriched in the circumventricular organs, choroid plexus, hypothalamus, cerebellum, and olfactory bulb. These studies on the insulin and IGF receptor in brain, add strong support to the suggestion that insulin and IGFs are important neuroactive substances, regulating growth, development, and metabolism in the brain.     

Differentiation and cell death: lessons from the immune system

The immune system provides a unique vantage point from which to view the interrelationship between differentiation and cell death, as apoptosis is a prominent feature of B- and T-lymphocyte development. Two common themes emerge from recent experimental observations. First, survival signals are crucial during the differentiation process. The upregulation of Bcl-2 during positive selection suggests that this molecule serves as a survival signal to maintain lymphoid homeostasis. Second, if cell death is repressed, cellular differentiation can occur in the absence of inductive signals.     

Fibrolast growth factors in the nervous system

Fibroblast growth factors (FGFs) exhibit widespread mitogenic and neurotrophic activities. Nine members of the family are currently known, and FGF-1 and FGF-2 are present in relatively high levels in CNS. FGF-1 is expressed by a subset of neuronal populations, while FGF-2 is expressed by astrocytes. FGF-1 and FGF-2 lack signal peptides and appear to be present mainly in inracellular compartmens. This suggests that the factors may act as initiators of a repair response after injury. Support for this notion comes from observations that FGF-1 and FGF-2 levels are low during critical phases of development, but high in the adult CNS. A family of transmembrane tyrosine kinase receptors (FGFRs) mediates the effects of FGFs. Four different genes coding for FGF receptors are currently known, three of which are expressed in cell type-specific patterns in the CNS The main receptor variants present in this tissue, however, can by themselves not distinguish between FGF-1 and FGF-2. Additional selectivity may be established by interaction of the FGFs and their receptors with select heparan proteoglycans (HSPGs). Therefore, the precise physiological role of FGFs is determined by the combination of cell type-specific patterns of expression of FGFs, FGFRs and HSPGs together with the mechanisms that regulate the extracellular availability of FGFs. 1994 John Wiley & Sons, Inc.     

Nutrition, insulin, insulin-like growth factors and cancer.

The incidence of colon, pancreatic, and kidney cancers, as well as aggressive prostate cancer in men, and breast and endometrial cancer in women is invariably high in Western countries. Nutritional and related factors have been typically implicated. This review presents a model integrating nutrition, insulin and IGF-1 physiology ("bioactive" IGF-1), and carcinogenesis based on the following: (1) insulin and the IGF-1 axis function in an integrated fashion to promote cell growth and survival; (2) chronic exposure to these growth properties enhances carcinogenesis; (3) factors that influence bioactive IGF-1 will affect cancer risk. The model presented here summarizes the data that chronic exposure to high levels of insulin and IGF-1 may mediate many of the risk factors for some cancers that are high in Western populations. This hypothesis may help explain some of the epidemiologic patterns observed for these cancers, both from a cross-national perspective and within populations. Of particular importance is that some of relevant factors are modifiable through nutritional and lifestyle interventions. Out of a variety of perspectives presented, nutritional manipulation through the insulin pathway may be more feasible than attempting to influence total IGF-1 concentrations, which are determined largely by growth hormone. Further study is required to test these conclusions.     

Structural features involved in the biological activity of insulin and the insulin-like growth factors: A27 insulin/BIGF-I

A synthetic insulin-like compound consisting of the A-chain of insulin extended at its carboxyl terminus with the hexapeptide "D-domain" of insulin-like Growth Factor II, linked via disulfide bonds to a B-chain corresponding to the "B-domain" of insulin-like Growth Factor I, has been examined for insulin-like metabolic activity and for mitogenic activity. The synthetic material (A27 insulin/BIGF-I) is less potent than insulin in metabolic assays, and less potent than both insulin and IGF-I in mitogenic assays. It is proposed that neither the "D-domain" nor the "B-domain" of the IGFs is a major contributor to mitogenic activity. Their presence in the same molecule does not result in significant growth-promoting activity.     

The early intracellular signaling pathway for the insulin/insulin-like growth factor receptor family in the mammalian central nervous system

Several studies support the idea that the polypeptides belonging to the family of insulin and insulin-like growth factors (IGFs) play an important role in brain development and continue to be produced in discrete areas of the adult brain. In numerous neuronal populations within the olfactory bulb, the cerebral and cerebellar cortex, the hippocampus, some diencephalic and brainstem nuclei, the spinal cord and the retina, specific insulin and IGF receptors, as well as crucial components of the intracellular receptor signaling pathway have been demonstrated. Thus, mature neurons are endowed with the cellular machinery to respond to insulin and IGF stimulation. Studies in vitro and in vivo, using normal and transgenic animals, have led to the hypothesis that, in the adult brain, IGF-I not only acts as a trophic factor, but also as a neuromodulator of some higher brain functions, such as long-term potentiation and depression. Furthermore, a trophic effect on certain neuronal populations becomes clearly evident in the ischemic brain or neurodegenerative disorders. Thus, the analysis of the early intracellular signaling pathway for the insulin/IGF receptor family in the brain is providing us with new intriguing findings on the way the mammalian brain is sculpted and operates.     

Brain targeting through the autonomous nervous system: lessons from prion diseases

The human central nervous system (CNS) is targeted by diverse pathogens that use distinct pathways to bypass the blood-brain barrier, such as trafficking into the brain via infected blood cells or using retrograde axonal transport through sensory or motor fibers. Prions are transmissible agents that induce a devastating subacute neurodegeneration when they successfully reach the CNS. Two recent studies focusing on pathways of prion neuroinvasion provide converging evidence that, in the case of peripheral transmission, such as human consumption of contaminated tissue, the infectious agent uses the sympathetic noradrenergic neurons to reach the CNS after early replication in lymphoid tissues.     

Fibroblast growth factors and their receptors in the central nervous system

Fibroblast growth factors (FGFs) and their receptors constitute an elaborate signaling system that participates in many developmental and repair processes of virtually all mammalian tissues. Among the 23 FGF members, ten have been identified in the brain. Four FGF receptors (FGFRs), receptor tyrosine kinases, are known so far. Ligand binding of these receptors greatly depends on the presence of heparan sulfate proteoglycans, which act as low affinity FGFRs. Ligand binding specificity of FGFRs depends on the third extracellular Ig-like domain, which is subject to alternative splicing. Activation of FGFRs triggers several intracellular signaling cascades. These include phosphorylation of src and PLC leading finally to activation of PKC, as well as activation of Crk and Shc. SNT/FRS2 serves as an alternative link of FGFRs to the activation of PKC and, in addition, activates the Ras signaling cascade. In the CNS, FGFs are widely expressed; FGF-2 is predominantly synthesized by astrocytes, whereas other FGF family members, e.g., FGF-5, FGF-8, and FGF-9, are primarily synthesized by neurons. During CNS development FGFs play important roles in neurogenesis, axon growth, and differentiation. In addition, FGFs are major determinants of neuronal survival both during development and during adulthood. Adult neurogenesis depends greatly on FGF-2. Finally, FGF-1 and FGF-2 seem to be involved in the regulation of synaptic plasticity and processes attributed to learning and memory.