Cell death in neural development

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Undergraduate BMS 381 Developmental neurobiology (AF lectures) Mind Map on Cell death in neural development, created by Kristi Brogden on 11/05/2014.
Kristi Brogden
Mind Map by Kristi Brogden, updated more than 1 year ago
Kristi Brogden
Created by Kristi Brogden over 10 years ago
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Resource summary

Cell death in neural development
  1. Ways to die
    1. Programmed cell death
      1. Apoptosis (Type 1)
        1. Most well studied
          1. Activated by extrinsic and intrinsic signals
            1. Important in development and disease
            2. Autophagy (Type 2)
              1. Less well studied
                1. Triggered by starvation, Protein aggregates
                  1. Important in disease
                    1. Tumor supressive
                      1. Neurodegeneration
                    2. Cytoplasmic (Type 3)
                    3. Necrosis
                    4. Apoptosis
                      1. Experiments
                        1. Knockout of ced-3 (Cell death abnormal) or egl-1 (Egg laying defective)
                          1. Too many cells
                            1. These are 'pro-apoptotic' proteins
                          2. Knockout of ced-9
                            1. Too much cell death
                              1. ''Anti-apoptotic" protein
                          3. Homologs of c.elegans cell death proteins conserved in vertebrates - regulate cell death
                            1. With some new elements
                              1. Bax (Bcl-2 associated)*
                                1. *Bcl-2homology(BH)domain proteins, including BH3-only, Bax
                                2. Caspase 9 (cysteine-aspartic acid protease)
                                  1. Two classes of caspase
                                    1. Executioner (or effector) caspase (e.g.caspase1)
                                      1. Initiator caspase (e.g. caspase 9)
                                      2. Caspase cascade
                                        1. At least 10 mammalian caspases
                                          1. Activated by auto-proteolysis
                                            1. Cascade effect
                                        2. Also have many other substrates
                                          1. DNA repair enzymes (PARP)
                                            1. Nuclear Lamins
                                              1. Maybe as many as 5% of cell proteins are targets!
                                              2. Two paths to activation
                                                1. Intrinsic Pathway
                                                  1. Pro-apoptotic BH domain proteins (Bax, Bak) permeablise mitochondrial wall
                                                    1. BalancebetweenBcl-2(anti- apoptotic) and Bax/Bak controls initiation
                                                      1. Released cytochrome c binds APAF-1, which binds and activates procaspase 9
                                                  2. Extrinsic pathway
                                                    1. Due to activation of Death Receptors by external ligands, e.g. TNF
                                                      1. Death receptors have intracellular Death Domains which bind adaptor proteins and procaspase 8 into a Death Inducing Signalling Complex (DISC), thus releasing active caspase 8
                                          2. Role in development
                                            1. Cell death is critical
                                              1. Loss of caspase 9 leads to exencephaly
                                                1. Why cell death?
                                                  1. PCD occurs in all tissues in development and throughout life
                                                    1. Why? (see Raff 1996, Cell v86, p173, for great discussion)
                                                    2. Size control
                                                      1. Most tissues are inter-dependent, you must keep things in proportion
                                                        1. Axons receive ‘trophic support’ from their targets (and vice-versa)
                                                        2. Removal of transient structures
                                                          1. E.g. subplate neurons in cortex, Ti1 axons in grasshopper limb: both are scaffolds for later axons and die once their job is done
                                                          2. Functional tuning - matching
                                                            1. Elimination of synapses
                                                              1. Viktor Hamburger 1900-2001 Student of Hans Spemann, mentor to Levi-Montalcini and Stanley Cohen, discoverers of NGF.
                                                                1. What factors underlie this interdependence?
                                                                  1. Neurotrophins
                                                                    1. lack of NGF promotes survival and in some contexts its absence actively promotes cell death.
                                                                      1. Over expression of p75NTR in Trk-expressing cells drives cell death
                                                                        1. Lowered expression of p75NTR promotes cell survival
                                                                          1. Binding of a neurotrophin to p74NTR in the absence of its appropriate Trk drives death
                                                                            1. p75NTR acts as a complex ‘death switch’ to tune neuronal survival to innervation of appropriate targets
                                                                              1. Because of its 'death switch' properties, P75NTR is known as a 'dependence receptor'
                                                                                1. There are now a large group of ‘dependence receptors’ defined by their ability to induce PCD in the absence of their respective ligands via caspase- dependent cleavage of their ICDs to release, poorly- defined, proapoptotic peptides
                                                                                  1. Interestingly, many of the identified dependence receptors are known guidance receptors (also include EphA4 and TrkC)
                                                                                    1. DCC = Deleted in Colon Cancer
                                                                        2. Electrical activity can also modify response to death signals through activation of neurotrophin expression
                                                              2. Its not all about cells dying
                                                                1. The pruning back of initially exuberant growth is a widespread feature of NS development
                                                                  1. e.g. cortico-spinal and cortico-collicular projections are initially similar, but are differentially pruned
                                                                    1. Many features of pruning are shared with Wallerian degeneration and with apoptosis, including
                                                                      1. Cell fragmentation
                                                                        1. Clearing by phagocytosis
                                                                          1. Led to the speculation that PCD pathways may be involved in both...
                                                                            1. Local caspase activity directs pruning
                                                                              1. DRONC is the caspase9 (ie initiator caspase) equivalent in drosophila
                                                                                1. Dendrites of local sensory neurons are pruned by local degeneration, involving branch severing, blebbing and fragmentation cf. Wallerian deg
                                                                                  1. Bloackade of DRONC (Lof or DN) blocks pruning
                                                                                    1. A reporter of caspase activation (based on PARP, an Effector caspase substrate), shows local activity at sites of branch severing
                                                                                      1. Evidence suggests caspases do not initiate severing of branches but are involved in the subsequent process of engulfment by phagocytes
                                                                                      2. Caspases also involved in axon degeneration
                                                                            2. See ppt for last 4 slides
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