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Cell biology in neuroscience: Death of developing neurons: new insights and implications for connectivity.

Dekkers MP, Nikoletopoulou V, Barde YA - J. Cell Biol. (2013)

Bottom Line: Recent discoveries now help to understand why only some developing neurons selectively depend on NGF.They also indicate that the survival of most neurons in the central nervous system (CNS) is not simply regulated by single growth factors like in the PNS.Additionally, components of the cell death machinery have begun to be recognized as regulators of selective axonal degeneration and synaptic function, thus playing a critical role in wiring up the nervous system.

View Article: PubMed Central - HTML - PubMed

Affiliation: Biozentrum, University of Basel, 4056 Basel, Switzerland.

ABSTRACT
The concept that target tissues determine the survival of neurons has inspired much of the thinking on neuronal development in vertebrates, not least because it is supported by decades of research on nerve growth factor (NGF) in the peripheral nervous system (PNS). Recent discoveries now help to understand why only some developing neurons selectively depend on NGF. They also indicate that the survival of most neurons in the central nervous system (CNS) is not simply regulated by single growth factors like in the PNS. Additionally, components of the cell death machinery have begun to be recognized as regulators of selective axonal degeneration and synaptic function, thus playing a critical role in wiring up the nervous system.

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Related in: MedlinePlus

Core components of the apoptotic machinery. The likelihood that a neuron undergoes apoptosis is determined by the interplay of the tightly interlinked apoptotic machinery, many components of which are highly conserved between species. The critical, and often terminal, step in programmed cell death is the proteolytic activation of the executor caspases (such as caspase 3, 6, 7) by the initiator caspases (i.e., caspase 8, 9, and 10; Riedl and Salvesen, 2007). In mammalian cells, initiation of the executor caspases is regulated by two distinct protein cascades: the intrinsic pathway, also known as the mitochondrial pathway, and the extrinsic pathway. The intrinsic pathway integrates a number of intra- and extracellular signal modalities, such as redox state (for example, the reactive oxygen species; Franklin, 2011), DNA damage (Sperka et al., 2012), ER stress (Puthalakath et al., 2007) and growth factor deprivation (Deckwerth et al., 1998; Putcha et al., 2003; Bredesen et al., 2005), or activation of the p75NTR neurotrophin receptor by pro-neurotrophins (Nykjaer et al., 2005). The stressors converge onto pro- and anti-apoptotic members of the Bcl-2 protein family (for example: BCL-2, BCL-Xl, BAX, and tBID; Youle and Strasser, 2008). These proteins regulate the release of cytochrome c from mitochondria, which activates the initiator caspase 9 through Apaf1 (Riedl and Salvesen, 2007). The extrinsic pathway links activation of ligand-bound death receptors (such as Fas/CD95 and TNFR) to the initiator caspase 8 and 10, through formation of the death-inducing signaling complex (DISC; LeBlanc and Ashkenazi, 2003; Peter and Krammer, 2003). Together with additional regulatory elements (including the Inhibitors of apoptosis proteins [IAP]; Vaux and Silke, 2005) and cFLIP (Scaffidi et al., 1999; Wang et al., 2005), the apoptotic machinery forms a balance that determines the propensity of the neuron to undergo apoptosis.
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fig1: Core components of the apoptotic machinery. The likelihood that a neuron undergoes apoptosis is determined by the interplay of the tightly interlinked apoptotic machinery, many components of which are highly conserved between species. The critical, and often terminal, step in programmed cell death is the proteolytic activation of the executor caspases (such as caspase 3, 6, 7) by the initiator caspases (i.e., caspase 8, 9, and 10; Riedl and Salvesen, 2007). In mammalian cells, initiation of the executor caspases is regulated by two distinct protein cascades: the intrinsic pathway, also known as the mitochondrial pathway, and the extrinsic pathway. The intrinsic pathway integrates a number of intra- and extracellular signal modalities, such as redox state (for example, the reactive oxygen species; Franklin, 2011), DNA damage (Sperka et al., 2012), ER stress (Puthalakath et al., 2007) and growth factor deprivation (Deckwerth et al., 1998; Putcha et al., 2003; Bredesen et al., 2005), or activation of the p75NTR neurotrophin receptor by pro-neurotrophins (Nykjaer et al., 2005). The stressors converge onto pro- and anti-apoptotic members of the Bcl-2 protein family (for example: BCL-2, BCL-Xl, BAX, and tBID; Youle and Strasser, 2008). These proteins regulate the release of cytochrome c from mitochondria, which activates the initiator caspase 9 through Apaf1 (Riedl and Salvesen, 2007). The extrinsic pathway links activation of ligand-bound death receptors (such as Fas/CD95 and TNFR) to the initiator caspase 8 and 10, through formation of the death-inducing signaling complex (DISC; LeBlanc and Ashkenazi, 2003; Peter and Krammer, 2003). Together with additional regulatory elements (including the Inhibitors of apoptosis proteins [IAP]; Vaux and Silke, 2005) and cFLIP (Scaffidi et al., 1999; Wang et al., 2005), the apoptotic machinery forms a balance that determines the propensity of the neuron to undergo apoptosis.

Mentions: Programmed cell death occurs throughout life, as cell turnover is part of homeostasis and maintenance in most organs and tissues. The situation in the nervous system is principally different, as the vast majority of neurons undergo their last round of cell division early in development. Soon after exiting the cell cycle, neurons start elongating axons to innervate their targets. It is during this period that they are highly susceptible to undergo programmed cell death: a large percentage, as much as 50% in several ganglia in the peripheral nervous system (PNS) as well as in various central nervous system (CNS) areas, is eliminated around the time that connections are being made with other cells. Later in development, the propensity of neurons to initiate apoptosis progressively decreases. The likelihood for a neuron to undergo apoptosis seems to be determined by a tightly regulated apoptotic machinery (summarized in Fig. 1). Therefore, modulation of the expression levels or the activity of components of this apoptotic balance changes the sensitivity to death-promoting cues, allowing temporal restriction of cell death.


Cell biology in neuroscience: Death of developing neurons: new insights and implications for connectivity.

Dekkers MP, Nikoletopoulou V, Barde YA - J. Cell Biol. (2013)

Core components of the apoptotic machinery. The likelihood that a neuron undergoes apoptosis is determined by the interplay of the tightly interlinked apoptotic machinery, many components of which are highly conserved between species. The critical, and often terminal, step in programmed cell death is the proteolytic activation of the executor caspases (such as caspase 3, 6, 7) by the initiator caspases (i.e., caspase 8, 9, and 10; Riedl and Salvesen, 2007). In mammalian cells, initiation of the executor caspases is regulated by two distinct protein cascades: the intrinsic pathway, also known as the mitochondrial pathway, and the extrinsic pathway. The intrinsic pathway integrates a number of intra- and extracellular signal modalities, such as redox state (for example, the reactive oxygen species; Franklin, 2011), DNA damage (Sperka et al., 2012), ER stress (Puthalakath et al., 2007) and growth factor deprivation (Deckwerth et al., 1998; Putcha et al., 2003; Bredesen et al., 2005), or activation of the p75NTR neurotrophin receptor by pro-neurotrophins (Nykjaer et al., 2005). The stressors converge onto pro- and anti-apoptotic members of the Bcl-2 protein family (for example: BCL-2, BCL-Xl, BAX, and tBID; Youle and Strasser, 2008). These proteins regulate the release of cytochrome c from mitochondria, which activates the initiator caspase 9 through Apaf1 (Riedl and Salvesen, 2007). The extrinsic pathway links activation of ligand-bound death receptors (such as Fas/CD95 and TNFR) to the initiator caspase 8 and 10, through formation of the death-inducing signaling complex (DISC; LeBlanc and Ashkenazi, 2003; Peter and Krammer, 2003). Together with additional regulatory elements (including the Inhibitors of apoptosis proteins [IAP]; Vaux and Silke, 2005) and cFLIP (Scaffidi et al., 1999; Wang et al., 2005), the apoptotic machinery forms a balance that determines the propensity of the neuron to undergo apoptosis.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3824005&req=5

fig1: Core components of the apoptotic machinery. The likelihood that a neuron undergoes apoptosis is determined by the interplay of the tightly interlinked apoptotic machinery, many components of which are highly conserved between species. The critical, and often terminal, step in programmed cell death is the proteolytic activation of the executor caspases (such as caspase 3, 6, 7) by the initiator caspases (i.e., caspase 8, 9, and 10; Riedl and Salvesen, 2007). In mammalian cells, initiation of the executor caspases is regulated by two distinct protein cascades: the intrinsic pathway, also known as the mitochondrial pathway, and the extrinsic pathway. The intrinsic pathway integrates a number of intra- and extracellular signal modalities, such as redox state (for example, the reactive oxygen species; Franklin, 2011), DNA damage (Sperka et al., 2012), ER stress (Puthalakath et al., 2007) and growth factor deprivation (Deckwerth et al., 1998; Putcha et al., 2003; Bredesen et al., 2005), or activation of the p75NTR neurotrophin receptor by pro-neurotrophins (Nykjaer et al., 2005). The stressors converge onto pro- and anti-apoptotic members of the Bcl-2 protein family (for example: BCL-2, BCL-Xl, BAX, and tBID; Youle and Strasser, 2008). These proteins regulate the release of cytochrome c from mitochondria, which activates the initiator caspase 9 through Apaf1 (Riedl and Salvesen, 2007). The extrinsic pathway links activation of ligand-bound death receptors (such as Fas/CD95 and TNFR) to the initiator caspase 8 and 10, through formation of the death-inducing signaling complex (DISC; LeBlanc and Ashkenazi, 2003; Peter and Krammer, 2003). Together with additional regulatory elements (including the Inhibitors of apoptosis proteins [IAP]; Vaux and Silke, 2005) and cFLIP (Scaffidi et al., 1999; Wang et al., 2005), the apoptotic machinery forms a balance that determines the propensity of the neuron to undergo apoptosis.
Mentions: Programmed cell death occurs throughout life, as cell turnover is part of homeostasis and maintenance in most organs and tissues. The situation in the nervous system is principally different, as the vast majority of neurons undergo their last round of cell division early in development. Soon after exiting the cell cycle, neurons start elongating axons to innervate their targets. It is during this period that they are highly susceptible to undergo programmed cell death: a large percentage, as much as 50% in several ganglia in the peripheral nervous system (PNS) as well as in various central nervous system (CNS) areas, is eliminated around the time that connections are being made with other cells. Later in development, the propensity of neurons to initiate apoptosis progressively decreases. The likelihood for a neuron to undergo apoptosis seems to be determined by a tightly regulated apoptotic machinery (summarized in Fig. 1). Therefore, modulation of the expression levels or the activity of components of this apoptotic balance changes the sensitivity to death-promoting cues, allowing temporal restriction of cell death.

Bottom Line: Recent discoveries now help to understand why only some developing neurons selectively depend on NGF.They also indicate that the survival of most neurons in the central nervous system (CNS) is not simply regulated by single growth factors like in the PNS.Additionally, components of the cell death machinery have begun to be recognized as regulators of selective axonal degeneration and synaptic function, thus playing a critical role in wiring up the nervous system.

View Article: PubMed Central - HTML - PubMed

Affiliation: Biozentrum, University of Basel, 4056 Basel, Switzerland.

ABSTRACT
The concept that target tissues determine the survival of neurons has inspired much of the thinking on neuronal development in vertebrates, not least because it is supported by decades of research on nerve growth factor (NGF) in the peripheral nervous system (PNS). Recent discoveries now help to understand why only some developing neurons selectively depend on NGF. They also indicate that the survival of most neurons in the central nervous system (CNS) is not simply regulated by single growth factors like in the PNS. Additionally, components of the cell death machinery have begun to be recognized as regulators of selective axonal degeneration and synaptic function, thus playing a critical role in wiring up the nervous system.

Show MeSH
Related in: MedlinePlus