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1、1,Neurotrophic factors and Their receptors,Huang Shu-Hong Institute of neurobiology,2,For decades, scientists believed that brain cells of the central nervous system could not regrow following damage due to trauma such as head injury or disorders such as Alzheimers disease. Treatments did not exist.
2、 The outlook was bleak.,3,But now that thinking has been turned upside down. Scientists recently have discovered a whole family of proteins called neurotrophic factors. These proteins play a crucial role in the development and survival of nerve cells, or neurons, and in supporting adult neurons to k
3、eep them healthy throughout life.,4,1934: Victor Hamburger discovered that removal of a limb bud resulted in reduced numbers of sensory and motor neurons in the spinal cord.,The neurotrophic factor hypothesis,5,Effect of Removing or Augmenting Neural Targets on the Survival of Related Neurons,PN2309
4、2.JPG,1939: Victor Hamburger showed that transplantation of a supernumerary limb resulted in increased numbers of sensory and motor neurons in the spinal cord.,6,Based on his limb-bud experiments, V. Hamburger hypothesized that the targets of innervating neurons provide signals that recruit undiffer
5、entiated cells to develop into sensory or motor neurons.,(he was wrong),In 1942, Levi-Montalcini and Levi proposed that target derived signals maintain survival of differentiating neurons. In 1949, Hamburger and Levi-Montalcini repeated the limb bud experiments and found that their results supported
6、 the neurotrophic hypothesis. Hamburger, V. and Levi-Montalcini, R. (1949) J. Exp. Zool. 111: 457-502.,The neurotrophic factor hypothesis,7,8,1954: neurite outgrowth assay, extract,+ extract,1969: NGF purified to homogeneity,Stanley Cohen,Rita Levi-Montalcini,1986: Levi-Montalcini and Cohen split th
7、e Nobel prize for Physiology or Medicine “for their discovery of growth factors”,1960: NGF purified,9,NGF: sympathetic neurons and some sensory neurons,(CNS neurons do not require NGF for survival),BDNF: NGF-related factor purified in 1982 from pig brain (shares 50% homolog with NGF),NT-3 and NT-4/5
8、: were obtained by PCR cloning,All these factors are synthesized as 250 aa precursors that are processed into 120 aa proteins,The main List of Neurotrophic Factors,10,Neurotrophins BDNF (brain derived neurotrophic factor) on cortical neurons,11,12,13,14,Trk receptor signaling,When a neurotrophin bin
9、ds to a trk receptor, the kinase domain is activated resulting in autophosphorylation.,Autophoshorylation results in further activation of the kinase domain, leading to activation of three potential signaling cascades:,MAPK,PI3K,PLC-g,15,16,Other neurotrophic Factors,17,18,Structure of neurotrophic
10、Factor receptors,19,Alternative splicing generates many Trk receptor isoforms,Roux and Barker (2002) Prog Neurobiol 67:203-233,NGF KD for TrkA=10-11M,20,p75NTR structure,NGF KD=10-9M (all neurotrophins can bind p75NTR),Roux and Barker (2002) Prog Neurobiol 67:203-233,21,Models for Trk and p75NTR int
11、eraction,Chao and Bothwell (2002) Neuron 33:9-12,22,The effect of NT/NTR knockouts on neurons in the DRG,Farias et al. (2002) Brain Res Bull 57:809-816,23,Our axons can be 1 m in length-how does the neurotrophin/receptor complex signal to the neuronal cell body?,Miller and Kaplan (2001) Neuron 32:76
12、7-770,24,Campenot, RB (1977) Local control of neurite development by nerve growth factor. Proc Natl Acad Sci U S A. 74(10):4516-9.,(A method that can be used to study how NTs added to distal axons signal retrogradely),Miller and Kaplan (2001) Neuron 32:767-770,NGF,+K252a,25,26,Activated Trk can sign
13、al locally and retrogradely using different signalling pathways,Miller and Kaplan (2001) Neuron 32:767-770,Slow (2-20 mm/hr),27,Differential control of TrkA trafficking and signaling may also be the basis for the different functions of NGF and NT-3,Kuruvilla et al. (2004) Cell 118: 243-255,28,In vit
14、ro assays have shown that NTs enhance both axonal and dendritic growth In vivo, the situation is more difficult to study,Why? In standard knockouts, it is difficult to separate the survival effects of NTs from their effects on the morphology of neurons. This problem has begun to be addressed by usin
15、g conditional knockouts, or by crossing NT knockouts with mouse mutants lacking pro-apoptotic genes. Recent evidence from these kinds of experiments suggests that long distance peripheral sensory axon growth in vivo is NT-dependent.,29,NTs roles in neuronal development and function,NTs are expressed
16、 in regions of the developing embryo that are traversed by sensory axons en route to their targets. NTs affect the proliferation and differentiation of CNS neuroepithelial progenitors, neural crest cells, and progenitors of enteric neurons in vitro (and in some cases also confirmed in vivo). In the
17、CNS, BDNF/TrkB signaling is implicated in the development and maintenance of cortical circuits.,30,NTs in the CNS,The highest levels of NTs are found in the hippocampus,Lindsay et al. (1995) Trends Neurosci 17:182-190.,31,Cytokines and Growth Factors in the Nervous System,CNTF, LIF (oncostatin M, ca
18、rdiotrophin-1): neuropoietic cytokines. These factors may be important in neuronal response to injury. GDNF, neurturin, artemin, persephin: exhibit distant homology with the TGF-b family. They signal through a receptor complex composed of the Ret tyrosine kinase and a GPI-linked binding subunit (GFR
19、a family; GFRa1, a2, a3, and a4). These factors are potent axon-promoting growth factors in vivo for developing sympathetic and parasympathetic neurons.,32,Summary,Neurotrophic factors play essential roles in the developing and mature nervous system. Now more than 50 years old, this field of study c
20、ontinues to contribute breakthrough discoveries regarding the fundamental biology of cell-cell communication and the development and maintenance of the most complex and elegant biological machine - the brain. Neurotrophic factors influence cell proliferation, survival, differentiation, migration, ax
21、on and dendrite growth, synaptic plasticity and the interactions of neuronal and glial cells.,33,What is a growth factor ? What is a trophic factor ?,DEFINITION Growth factors include substances that stimulate cells to divide (hyperplasia) or increase in size (hypertrophy). Many growth factors are n
22、ow known to exist Trophic factors include those substances that have effects on cell differentiation, cell survival, expression of a specific cellular phenotype (e.g. a cell becomes an inhibitory or an excitatory neuron), cellular morphological plasticity, as well as cell hypertrophy including, for
23、example, the induction of neurite extention (also considered a “trophic“ action). Importantly, some growth factors may also act as trophic factors and viceversa and each growth/trophic factor may have a specific combination of cellular effects.,34,Neurotrophic factors,Neurotrophic factors are endoge
24、nous soluble proteins regulating survival, growth, morphological and synaptic* plasticity, or synthesis of proteins for differentiated functions of neurons. (* synaptic plasticity = regulation of the transmission activity at the level of the synapse),35,Which cell sythesizes the neurotrophic factors ?,Neurotrophic factors are produced by all cells of the nervous system, including neurons, glial cells, ependimal cells, blood vessels endothelial cells and cells from innervated tissues such as muscles, epidermis, etc,