On Apoptosis in Development

Apoptosis means doom for an individual cell. As such we tend to automatically assume that apoptosis is a Bad Thing, but in reality apoptosis often is quite necessary for normal physiological function at the organism level. In order for our bodies to maintain the homeostasis that defines so many of our cellular processes, we have to sacrifice some cells. As it turns out, we actually wind up sacrificing enormous numbers of cells every day. Worn out red blood cells, dangerously self-reactive lymphocytes, individual columnar epithelial cells and others. These processes are tightly regulated, so much so that most cell types actually require biochemical signals from neighboring cells, tissues, or even distant organs just to tell them to keep living. The anti-apoptotic survival signals can fall below a threshhold value and/or be overridden by pro-apoptotic stimuli, which normally results in swift induction of the apoptotic program. When individual cells develop mutations that deafen them to these signals, they become dangerous proliferation-happy pre-cancerous cells more interested in their own survival than that of their constituent organism.

Figure A: TUNEL histochemical staining in murine liver, brown cell is apoptotic.

The apoptotic program ultimately results in highly oxidative and degradative enzymes (such as proteases) hidden away in the mitochondria being released into the cytoplasm to wreak havoc. Usually the raw material of a dying cell is tidily absorbed by its neighbors to be recycled. I've always imagined mitochondria as pulsing with a low, gentle buzz in normal cellular physiology with occassional metallic pings as statistical flucuations in the net free energy of electrons falling down the electron transport chain is captured in ATP. Following this, I think the sound of caspase-8 et al slicing open the mitochondria would be like the initial panicked braking shriek of a train loaded with Furbies who are quickly drowned out in the self-amplifying roar like a tornado grinding through a gravel pit as the apoptotic effector enzymes set to work dissolving the cell from within.

Apoptosis is absolutely essential not just to adult homeostasis, but also to normal ontogeny. Without apoptosis organs would fail to separate, fingers would remain stuck together, and many other things would go very, very wrong. There are 2 families of intracellular proteins that battle to determine whether or not a cell will become apoptotic: the (generally) pro-apoptotic Bcl-2 family and the (generally) anti-apoptotic IAP family. Conveniently, IAP stands for Inhibitor of Apoptosis Protein. A recent review by Dr. O'Riordan et al discussed the diverse and essential roles for IAP proteins in normal tissue development across a wide range of model organisms. From ablated organ development in the absence of Diap1 in Drosophila larvae to stunted hematopoeitic developmental repertoire in the abscence of Survivin in mice, IAPs seem to be evolutionarily conserved signal transducers that integrate diverse extracellular signals into a coherent cellular action. Developmentally, the IAP proteins seem to be involved in everything from proper vascularization to chromosome stability, although it is important to note that direct modulation of apoptosis in developmental processes has only been established in invertebrates. Lack of any one of several IAPs in higher chordates has not been directly linked to developmental apoptosis, but several abnormal embryonic phenotypes and attenuated adult functional capacities have been demonstrated.

IAPs are grouped by the prescence of BIRs (baculovirus IAP repeats) and many also have RING domains. Both motifs have been found to have zinc-finger conformations and the interaction of different sections of adjacent BIR motifs in some proteins, such as direct inhibition of pro-apoptotic caspases-3 and -7 by BIR2 of XIAP (X-linked inhibitor of apoptosis protein), has been found to modulate a number of diverse effects. These diverse effects are potentiated by the ubiquitin ligase activity that some RING domains have demonstrated. IAPs help the organism balance necessary apoptosis and unnecessary apoptosis, and because apoptosis is required for the homeostasis of most tissues the IAP family has been evolutionarily conserved and biochemically diversified. IAPs remain an active and engaging area of research that holds great promise in the treatment of pathologies from cancer to intracellular bacterial infections and underscore how a little sacrifice for the team by one cell can make a massive impact on the constituent organism's overall fitness.

IAPs have also been found to modulate innate immunity, which will be discussed in another post.

ORIORDAN, M., BAULER, L., SCOTT, F., & DUCKETT, C. (2008). Inhibitor of Apoptosis Proteins in Eukaryotic Evolution and Development: A Model of Thematic Conservation Developmental Cell, 15 (4), 497-508 DOI: 10.1016/j.devcel.2008.09.012

Additional Source: Molecular Biology of the Cell; Alberts et al; 4th ed.; pages 1010-1014

Apoptosis

Trouble was afoot in the sticky wastelands of the cytosol. The plasma membrane sky was turbulent overhead, sphingomyelin rafts swirling faster than normal as ear-splitting explosions rattled down the signal transduction cascades, amplifying as they arced off towards to distant mass hovering on the horizon. Something wasn't right there, either. The nucleus had been hurt badly in the last infection. It's latticed double envelope still bore the oxidative scars of the inflammatory reaction, the translocons feebly trying to properly refold with half of their functional domains blasted away. The mitochondria were rumbling, louder than normal, but perhaps they only seemed the louder because the endoplasmic reticulum and Golgi stacks were uncharacteristically quiet.

It was dark. Almost all the ATP had been hydrolyzed in the Inflammation, and now the mitochondria weren't producing any more--glucose and lipid transport had all but ceased. Even though they were still rumbling away...

This city was in trouble, and it knew it. The nation's dark Bim messengers were gathering quickly, clustering in ominous clouds with their Smacs while the wounded Bcl-ws could only drift aimlessly amid the sticky desert, observing.

Another explosion rattled down the signal transduction cascades, and with it phospolipid translocases began to fall in slow-motion, plunging into the boiling recesses of the peroxisomes. But this explosion didn't head towards the beaten nucleus; instead it flashed right into the hovering Bim/Smac clouds. A critical threshold had been reached...

The gloomy flocks rapidly dispersed and swarmed the mitochondria, diving into their wrinkled surfaces and rending their membranes. The mitochondrial rumbling rose in pitch, becoming a tortured kind of scream as the oxidative hellions broke loose of their matrix prison. Capsase and cytochome c erupted into the cell, colliding chaotically with everything else inside the cell, shattering the fragile secondary structures and motifs with their destructive oxidations.

The city was awash with the death-cries of the wounded. The nucleus gradually imploded, caving inwards and collapsing into the flailing centrioles and endoplasmic reticulum. The integral proteins of the plasma membrane sky plummeted further downward, rending the sticky desert with their cries as massive holes opened up in the sky and neighboring cities began to suck up the rubble, even before the city had been completely destroyed.

Within minutes, it was all over. Everything was gone, and it was as though the city had never existed in the first place...