class 10 synapse formation

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Information about class 10 synapse formation

Published on October 16, 2007

Author: Nellwyn


Slide1:  Emergence of the concept of Synapse Formation Molecules: Chemotaxis Slide2:                                                   Figure 1. Rita Levi-Montalcini (1990), Italy. Discovery of NGF Slide3:  Photomicrographs of sensory ganglia removed from an eight-day-old chick embryo and cultured for 24 h at 37 °C. Ganglia were cultured (a) in a medium containing no nerve growth factor (NGF) and (b) in a medium containing 10 ng ml−1 of NGF. Note that only the ganglion that was exposed to NGF displays a dense halo of nerve fibers. Reprinted, with permission, from Ref. [14]. © (1964) American Association for the Advancement of Science ( Slide4:  The remarkable accomplishments in developmental neurobiology within the past 60 years have depended on two things: (i) a succession of original histochemical and immunohistochemical methodologies for identifying pathways in the nervous system with increasing precision and sensitivity, and (ii) the discovery of growth factors for neurons. Growth factors are naturally occurring, essential biological mediators that promote cell growth, differentiation, survival and function in specific nerve cell populations. The discovery of nerve growth factor (NGF) by Rita Levi-Montalcini in the 1950s represents an important milestone in the processes that led to modern cell biology. NGF was the first growth factor identified, for its action on the morphological differentiation of neural-crest-derived nerve cells. Later, its effect on neuronal cells of the peripheral and central nervous systems, and on several non-neuronal cells was also determined. Thus, Levi-Montalcini's work on NGF represents, as acknowledged by the Nobel Prize Assembly in its press release of 13 October 1986, ‘a fascinating example of how a skilled observer can create a concept out of apparent chaos’. Slide5:  The NGF story began in 1949, after Victor Hamburger showed the results obtained by one of his postgraduate students, Elmer Bueker, to Levi-Montalcini. Bueker had observed that, after the implantation of a small fragment of malignant mouse tumor into the body walls of three-day-old chick embryos, sensory fibers invaded the mouse tumor. He was investigating whether homogeneous neoplastic tissue could act as a substitute for a complex limb in supporting the development of the spinal cord and sensory ganglia, and found that the transplanted tumor grew well in chick embryos, that nearby peripheral nerves invaded the tumor mass and that adjacent dorsal root ganglia were markedly enlarged. Bueker hypothesized that this effect was due to the rapidly expanding tumor enabling the sensory fibers to branch in a larger field than the embryonic tissues that had been replaced with the neoplastic cells [8]. This hypothesis did not convince Levi-Montalcini who, with the permission of Bueker, reinvestigated the effects of transplanting two mouse sarcoma tissues into a chick embryo. Working on serial histological sections of chick embryos that were stained using Cajal's silver technique for identifying and charting the connection of many different neuronal circuits, Levi-Montalcini found that the tumor tissues induced hyperinnervation of internal organs, and she hypothesized that the transplanted tissues released a diffusible agent that stimulated the growth and differentiation of the developing nerve cells ( Figure 2). She determined that a reliable bioassay to both quantify and demonstrate the biological activity of this, as yet unknown, substance present in the tumor mass was essential to sustain her hypothesis. She carried out these studies during a sabbatical period in Brazil, in the laboratory of Herta Meyer (University of Brazil;, who was an expert in cell culture techniques, and a former student of Giuseppe Levi. There, Levi-Montalcini investigated a method to quantify the stimulating effect of a tumor on neural cells. She conducted tissue culture experiments using sensory and sympathetic ganglia of chick embryos that were exposed to fragments and/or extracts of tumor tissue. She observed that the tumor could release a diffusible factor that promoted neurite outgrowth directly (Figure 3), in addition to nerve cell differentiation [9, 10 and 11]. Furthermore, this effect was dose dependent, and Levi-Montalcini devised a semi-quantitative method for determining the biological activity of the substance released from the tumor tissue. Slide6:  Figure 2. Semi-diagrammatic reconstruction of a normal 11-day-old chick embryo (E 11N), an 11-day-old chick embryo carrying an intra-embryonic transplant of mouse sarcoma (S 37–81), and an 11-day-old chick embryo with a transplant of sarcoma 37 on the chorioallantoid membrane (S 37–220). Note the hyperplastic growth of the prevertebral ganglia in the embryos carrying tumor transplants. Visceral nerve fibers from these ganglia invade the nearby mesonephros. Abbreviations: A, adrenal; G, gonad; L, lung; M, mesonephros; PV, prevertebral ganglia; S, sensory nerves; Tu, tumor. Reprinted, with permission, from Ref. [10]. © (1952) New York Academy of Sciences, U.S.A. Slide7:  Figure 3. Eight-day-old sensory ganglia from chick embryos. (a) The ganglion, which faces a fragment of chick embryonic tissue (ct), shows fibroblasts but few nerve fibers. (b) Ganglion cultured in the presence of fragments of mouse sarcoma for 24 h. (c) Ganglion cultured in the presence of fragments of mouse sarcoma for 48 h. In (b) and (c), the ganglia, facing fragments of sarcoma (s), show the typical ‘halo’ effect elicited by the growth factor released from the sarcoma. In (c), note the first evidence of a neurotropic effect of the growth factor. Reproduced, with permission, from Ref. [7]. © (1986) The Nobel Foundation. Slide8:  In the early 1950s, Levi-Montalcini, in collaboration with the young biochemist Stanley Cohen at Washington University in St Louis, USA (who discovered epidermal growth factor and was co-winner of the Nobel Prize in 1986), set out a series of experimental approaches to characterize the biochemical properties of NGF. To determine whether the biologically active molecule was a nucleic acid or a protein, they performed experiments using snake venom (a rich source of phosphodiesterase) to destroy any nucleic acid. They observed that snake venom produced more neural outgrowth than that seen with cultures incubated with tumor extract. The finding that NGF was present in the venom led Cohen to realize that it might be worthwhile to look at the mammalian analog of the snake venom gland, the mouse salivary gland. In vitro studies with chick sensory ganglia showed this foresight to be well founded. Indeed, it was discovered that the mouse gland is a rich source of NGF [11 and 12] ( Figure 4) and, in 1960, owing to the high concentration of NGF in this gland, Levi-Montalcini and Cohen succeeded in isolating and purifying the molecule and demonstrating that it was a protein [13 and 14]. With the availability of large amounts of purified mouse salivary NGF, Levi-Montalcini and Cohen could produce large quantities of antibodies against NGF [15 and 16] and, through the use of these antibodies, they demonstrated the functional significance of NGF in the in vivo development of sympathetic and sensory ganglia. In 1970, Ruth Houge Angeletti and Ralph Bradshaw (Washington University in St Louis, USA) demonstrated that the NGF protein is part of a precursor, and that the processor enzyme remains associated to NGF to form a large, multimolecular complex defined as 7S NGF. The 7S complex consists of three different molecular species – the α subunit, the function of which is largely unknown; the γ subunit, which possesses protease activity; and the β subunit, which is the biologically active form of NGF [17]. Subsequent studies have revealed that NGF is a highly conserved molecule with a high interspecies homology, and its biological activity is regulated by two structurally unrelated receptors: a low-affinity receptor known as p75 NGF receptor, and the high-affinity gp140trkA receptor, which is a member of the trk family of tyrosine kinase receptors [18]. Using modern recombinant-DNA technology, the mouse and human genes encoding NGF were identified on the proximal short arm of chromosome 1. More recently, murine and human recombinant NGF has been produced and is available for basic and clinical studies Biological characterization of the NGF Slide9:  How nerve growth factor (NGF) might modulate nervous–endocrine–immune interaction. NGF released from tissue mast cells as a consequence of inputs from the nervous, immune or endocrine system can, in turn, influence the same system (locally or through the circulation). NGF released from mast cells might also function in an autocrine manner. Reproduced, with permission, from Ref. Slide10:  Neurotrophins influence dendritic arbors in the developing cerebral cortex. The cell on the left was transfected with the gene for green fluorescent protein (GFP) alone, the one on the right with GFP plus the gene encoding BDNF. Within a day, BDNF-transfected neurons grow elaborate dendritic branches, reminiscent of the NGF-induced halo in peripheral ganglia (see Figure 23.12B). (From Horch et al., 1999.) Discovery of BDNF Slide11:  During the 30 years or so that work with NGF showed it to fulfill all the criteria for a target-derived neurotrophic factor (see text), it became clear that NGF affected only a few specific populations of peripheral neurons. It was therefore presumed that other neurotrophic factors must exist that followed similar rules, but supported the survival and growth of other classes of neurons. In particular, whereas NGF was shown to be secreted by the peripheral targets of primary sensory and sympathetic neurons, other factors were presumably produced by target neurons in the brain and spinal cord that supported the central projections of sensory neurons. The serendipity of the mouse salivary gland and its extraordinary levels of NGF was not repeated for these additional factors, however, and the hunt for the neurotrophic factors presumed to act in the central nervous system proved to be a long and arduous one. Indeed, it was not until the 1980s that the pioneering work of Yves Barde, Hans Thoenen, and their colleagues succeeded in identifying and purifying a factor from the brain that they named brain-derived neurotrophic factor (BDNF). As with NGF, this factor was purified on the basis of its ability to promote the survival and neurite outgrowth of sensory neurons. However, BDNF is expressed at such vanishingly small levels that over a million-fold purification was necessary before the protein could be identified! Slide12:  Thereafter, microsequencing and recombinant DNA technology allowed rapid progress even from the scant amounts of purified BDNF protein that were available. By 1989, Barde's group had succeeded in cloning the cDNA for BDNF. Surprisingly—despite its entirely different origin and distinct neuronal specificity—BDNF turned out to be a close relative of NGF. Based on the homologies between the primary structures of NGF and BDNF, the following year six independent laboratories (including Barde's) reported the cloning of a third member of the neurotrophin family, neurotrophin-3 (NT-3). At present, four members of the neurotrophin family have been reported in a variety of vertebrate species (see text). Slide13:  Experiments on BDNF and other members of the neurotrophin family over last decade have supported the conclusion that the survival and growth of different neuronal populations in both the PNS and CNS is dependent on different neurotrophins, relationships that are mediated by expression of membrane receptors that are specific for each neurotrophin (see figure). However, the dramatic relationship between the survival of neuronal populations and neurotro-phins has not been found in the CNS, where BDNF, NT-3, and NT-4/5, as well as their receptors, are primarily expressed. The most striking demonstration of this difference has been in “knockout” mice in which individual genes encoding neurotrophins or Trk receptors have been deleted: While these genetic deletions have led to predictable deficits in the PNS (see text), they have generally had minimal impact on CNS structure and function. Thus, the part played by neurotrophins in the CNS remains much less certain. One possibility is that these neurotrophins are more involved in regulating neuronal differentiation and phenotype in the CNS than in supporting neuronal survival per se. In this regard, the expression of neurotrophins is tightly regulated by electrical and synaptic activity, suggesting that they may also influence experience-dependent processes during the formation of circuits in the CNS. Slide14:  Formation of synapses during 1) organism development 2) in adult age after denervation Historically, the synapse of choice has the Neuro Muscular Junction Slide15:  Two scientist started a series of pioneering experiments on nerve degeneration and regeneration between 1895 and 1907: Once more, John Langley, and F. Tello. The line of investigation was not continued for the subsequent 50 years, until Gutmann and Young initiated a series of experiments in 1944 that would eventually lead to the discovery of a series of chemotactic rules and other results, line of investigation that is still open and important to date Slide16:  Langley cuts some of the cranial nerves and other spinal nerves, allows a recovery time of a year and then rechecks the effect of nerve stimulation to determine Slide18:  Commenting on the relatively high specificity of the innervation that he found, Langley comments: "at the bottom then the phenomenon is a chemotactic one" Slide19:  The word chemotactic acquires a specific meaning in the words of Harrison (1910): Slide20:  Tello describes for the first time the detailed effect of denervation and the multiple reinnervation of regrowing NMJ fibers Slide23:  Only concomitant modern techniques Reveal the specificity of the NMJ reinnervation Slide25:  Discovery of post-to-presynaptic communication (Sanes, 1978), for the establishment of proper presynaptic ultrastructures Slide26:  A subestimation of the pre-post synaptic interactions in the process of synaptic formation is starting to appear only in the last decade Slide28:  From Kleinman and Reichardt, 1996 Slide29:  Discovery of the NJM growth factor MuSK Slide30:  Comparison between Langley's data and Sanes data obtained 80 years later

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