Apoptosis

Today's post is going to focus on cell death and pruning.  We are going to walk through the progressive and regressive processes that take place during brain development.

Some progressive events that take place during neuronal development include proliferation, axon guidance, and synapse formation.  Regressive events include apoptosis and axonal/dendritic/synaptic pruning.  Let's first take a look at the latter.

Both apoptosis and pruning are critical processes that sculpt the developing brain.

What are some factors that affect the survival of neurons during development?
Soluble factors include glia-derived and target-derived (retrograde) factors.  We also see afferent-derived (anterograde) factors, as well as hormones.

Types of cell death:
1.  Apoptosis: Leads to morphologic changes then cell death.  These changes include blebbing, loss of cell membrane asymmetry and attachment, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation. Unlike necrosis, apoptosis produces cell fragments called apoptotic bodies that surrounding cells are able to engulf and quickly remove before the contents of the cell can spill out onto surrounding cells and cause damage.*


2.  Necrosis: the premature death of cells and living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death. While apoptosis often provides beneficial effects to the organism, necrosis is almost always detrimental and can be fatal.*


Cell death machinery was first identified in C. Elegans.  With a total of only 959 cells, researchers found that 131 cells die during pruning, 26 of which are neurons.  Protein synthesis was crucial in determining whether a cell lived or died.  Anti-apoptotic proteins include Bcl-2 and Bcl-x.  Pro-apoptotic proteins include Bax, Caspase-9, Caspase-3, Apaf-1, and Cytochrome c.

Survival factors are NGFs, nerve growth factors, that aid in the survival of the cell.  Kind of self-explanatory.  Neurotrophin signaling activates anti-apoptotic genes and leads to survival.  From Wikipedia, "They [neurotrophins] belong to a class of growth factors, secreted proteins that are capable of signaling particular cells to survive, differentiate, or grow. Growth factors such as neurotrophins that promote the survival of neurons are known as neurotrophic factors. Neurotrophic factors are secreted by target tissue and act by preventing the associated neuron from initiating programmed cell death - thus allowing the neurons to survive. Neurotrophins also induce differentiation of progenitor cells, to form neurons."


Netrin-signaling is also anti-apoptotic.  


Sema/Plexin signaling is pro-apoptotic. 


As mentioned earlier, hormones also play a role in regulating cell death.  Metamorphosis in vertebrates and invertebrates is hormonally-regulated tissue deconstruction, associated with massive cell death and neuronal pruning.  Researchers have found evidence to suggest sexual dimorphism in circuits with regards to hormones.  One major study to show this involved bird mating songs.  They found that more neurons in the male birds were dedicated to mediating song acquisition compared to the females. Interestingly, they could induce masculinization of the female via injection of male-specific hormones.  


Neuronal Pruning: Pruning is a strategy often used to selectively remove exuberant neuronal branches and connections in the immature nervous system to ensure the proper formation of functional circuitry.  It can be small-scale and large-scale.  Small-scale pruning includes axosome shedding, lysosomal activity, activity-dependent pruning, and stochasticity.  You will see it in muscle cells and Purkinje neurons.  
Large-scale pruning is stereotyped/developmentally-regulated as well as activity-dependent.  


Take-away from this post:
1. Factors regulating axonal pruning:
- neural activity
- hormones
- guidance molecules - sema/plexins
- cohesin, ubiquitin-proteosome machinery, regulators of cytoskeletal dynamics, tx factors, caspases, RNA-binding proteins
2.  Regulation of regressive processes during neuronal development: Cross-talk between guidance mechanisms and cell death machinery
- guidance molecules as regulators of neuronal cell death
- cell death machinery (proteases, proteoltyic/lysosomal pathways) involved in axonal pruning.
- Pruning - local death of a neurite?  Cell death machinery is regulated by guidance cues.  


Ehhh, that was a long one.  
*Wikipedia