Early regional variations in motoneuron numbers arise by differential proliferation in the chick embryo spinal cord

Regional differences in the number of motoneurons in the spinal cord of the chick are thought to arise developmentally by region-specific cell death and cell migration. In this way, a numerically homogeneous motor column throughout the spinal cord is believed to be molded into the adult pattern. Region-specific differences in proliferation are not thought to play a significant role in this process. By counting motoneurons in serial sections throughout the rostral-caudal extent of the spinal cord on Embryonic Day 4 in the chick, we have found that the numerical variations in motoneurons in different spinal cord regions are already foreshadowed by this stage, which is before the onset of both cell death and the secondary migration of neurons out of the motor column. These results indicate that although nonproliferative events may contribute to the later regional variations in motoneuron numbers, the initial differences themselves are created early on by regionally specific proliferative events.     

Generation of electromotor neurons in Sternarchus albifrons: differences between normally growing and regenerating spinal cord

This study examines the regulation of the number of electromotor neurons during postnatal growth of the spinal cord in the gymnotiform teleost Sternarchus albifrons. It specifically asks whether a large overproduction of electromotor neurons and a wave of cell death, similar to those occurring during spinal cord regeneration in this species, play a role in the on-going growth at the caudal tip of the normal spinal cord. Neurons are produced from ependymal precursors at the caudal end of the spinal cord during both normal growth in the adult and regeneration of the spinal cord in this species. Previous studies have demonstrated that during spinal cord regeneration after amputation of the tail in Sternarchus, there is an initial massive (up to fivefold) overproduction of electromotor neurons, followed by a wave of cell death which reduces the number of these neurons to the normal level. In the present study, transverse sections through the caudalmost spinal segment of normal adult Sternarchus were examined. Proceeding rostrally from the caudal tip of the cord, the number of electromotor neurons increases monotonically to reach the normal number at a site 4-5 mm rostral to the caudal tip. Neither a massive overproduction of electromotor neurons nor a wave of neuronal death are observed during on-going growth of the normal spinal cord. The mechanisms by which the neuronal number is modulated are therefore different in the on-going normal growth of spinal cord versus regeneration of spinal cord in this species.     

Extracellular proteases and neuronal cell death.

Neuronal cell death occurs during development of the central nervous system as well as in pathological situations such as acute injury and progressive degenerative diseases. For instance, granule cells in the developing cerebellum and neuronal precursor cells in the cortex undergo programmed cell death, or apoptosis. There is currently strong debate conceming the mechanism of death in many degenerative events such as ischemia, blunt head trauma, excitotoxicity and neurodegenerative diseases, i.e. Alzheimer's disease. Neurons can die a necrotic death when the initial insult is too great; apoptosis requires "planning." For example, the cell death seen in the core of an ischemic infarct is necrotic, while in the surrounding penumbra region the death is probably apoptotic. Regardless of the degenerative pathway, damaged or dead neurons are a hallmark of many diseases including Alzheimer's, Parkinson's, glaucoma, ischemia and multiple sclerosis. Molecules such as cytokines, chemokines, reactive nitrogen/oxygen species, and proteases play an important role in promoting and/or mediating neurodegeneration. Proteases have been implicated in both physiological and pathological events, suggesting their intervention in key points when things go awry. In this review we will summarize recent findings linking extracellular proteases with neuronal cell death in both human diseases and their animal models.     

Induction of Apoptosis in Leukemia U937 Cells by 5′-Deoxy-5′-methylthioadenosine, a Potent Inhibitor of Protein Carboxylmethyltransferase

We found dramatic changes in leukemia U937 cells treated with 5′-deoxy-5′-methylthioadenosine (MTA), a potent inhibitor of protein carboxylmethyltransferase (protein methylase II). Initiation of cell death was observed by 1 day after MTA treatment, and it was induced in a dose- and time-dependent manner. However, cell viability measured by trypan blue exclusion was not consistent with the actual percentage of cell death. These results indirectly indicated that the type of cell death is apoptosis rather than necrosis. Nuclear fragmentation and DNA condensation of MTA-treated U937 cells were analyzed by both fluorescent and electron microscopy. MTA-treated cells first began to arrest in the M phase of the cell cycle, and they then exhibited a mitotic-like nuclear fragmentation process with partially membraneless chromatin. Furthermore, agarose gel electrophoresis of DNA extracted from cells treated with MTA showed DNA laddering with production of fragments of approximately 200 bp multiples. These studies indicated that cell death induced by MTA has the characteristics of apoptosis, although nuclear fragmentation is atypical. It seems likely that the process of apoptosis in U937 cells induced by MTA correlates with incomplete assembly of the nuclear envelope, since MTA itself could inhibit the carboxylmethylation of nuclear lamin B and delayed incorporation of lamin B into the nuclear envelope.     

Interleukin-3 and bryostatin 1 mediate rapid nuclear envelope protein phosphorylation in growth factor-dependent FDC-P1 hematopoietic cells. A possible role for nuclear protein kinase C

Interleukin-3 (IL-3) is a lymphokine which stimulates the proliferation of normal and transformed multilineage hematopoietic cells. Recently we reported that bryostatin 1, a macrocyclic lactone and potent activator of protein kinase C, could stimulate normal multipotential hematopoietic progenitor cells in vitro in the absence of added polypeptide growth factors. We have now used the murine IL-3-dependent cell line FDC-P1, derived from normal murine marrow cells, to examine the early biochemical events associated with stimulation of hematopoietic cells. We find that both IL-3 and bryostatin 1 are mitogenic and stimulate the growth of FDC-P1 cells. Cells grown for extended periods in the presence of bryostatin 1 (1 nM) alone retain IL-3 responsiveness, indicating that bryostatin 1 does not induce an IL-3-independent state. Protein phosphorylation studies in cells treated with either IL-3 or bryostatin 1 indicate that both stimulators can mediate the rapid (within 5 min) serine-specific phosphorylation of several nuclear envelope polypeptides, including lamin B. Both IL-3- and bryostatin 1-mediated nuclear envelope phosphorylation is dose-dependent, occurring at concentrations which are mitogenic to FDC-P1 cells. The extent of nuclear envelope phosphorylation mediated by IL-3 and bryostatin 1 correlates with the mitogenic response. Furthermore, both mitogens mediate the rapid immunologic translocation of protein kinase C to the nuclear envelope where phosphorylation occurs. These data indicate that the early mitogenic signal(s) generated by IL-3 and bryostatin 1 may converge at the level of the nuclear envelope, perhaps through a protein kinase C-like activity which mediates phosphorylation of specific nuclear envelope polypeptides such as lamin B.     

Cell cycling and DNA replication in a mutant blocked in cell division in the nematode Caenorhabditis elegans

The postembryonic development of the nematode Caenorhabditis elegans has been described at the level of individual cell lineages. A mutant of postembryonic development, lin-5 II, causes a failure of postembryonic nuclear and cell divisions. Mitosis in living animals is seen by light microscopy to proceed through prophase and nuclear envelope breakdown, but an abnormal-looking metaphase plate forms in the mutant, after which the interphase nuclear morphology reappears until the next attempted round of division. The precursor cells which give rise to the ventral nerve cord have been studied in lin-5. In the wild type these cells divide asymmetrically to give six descendants (one hypodermal cell and five neurons). In the mutant these precursors accumulate approximately six times the diploid quantity of DNA within a single nucleus, while attempting mitosis up to three times. These polyploid cells display characteristics of the cells they would have produced ordinarily.     

Iron containing nuclear inclusions in human pigmentary cirrhosis (author's transl)]

In human pigmentary cirrhosis nuclear (pseudo-)inclusions of cytoplasmic material, containing less or more degenerated and therefore faintly stained hemosiderin granules, are to be observed. But sometimes there are also finely fibrillar or granular proteinaceous materials, stainable by the Prussian-blue reaction, lying between the chromatin-strands or occupying the whole nucleus and displacing the chromatin to the nuclear envelope (margination of chromatin). Such uncoloured substances may condense into homogeneous masses and nearly hexagonal (0r related) crystals with a diameter up to 14 micron and a yellow-brownish colour, giving a strongly positive PERL's reaction. In contrast to the preceding stages intranuclear crystals of this kind have been observed in one case only. After destruction of the nuclear envelope and the marginated chromatin the crystals are lying free in the cytoplasm and later on, the cytoplasm being destroyed too, they may be ingested by von Kupffer cells. All the iron containing crystals, to be found in the cytoplasm, derive from former intranuclear inclusions. The intranuclear deposits of iron containing protein are interpreted as ferritin-aggregates. It is supposed that ferritin molecules, built up in the cytoplasm, do enter the nucleus via the pores of the nuclear envelope. Such an event not only signalizes a cytopathologic reaction but in turn may give rise to such additional cytopathologic lesions as cell shrinking and cell death.     

Staurosporine treatment and serum starvation promote the cleavage of emerin in cultured mouse myoblasts: involvement of a caspase-dependent mechanism.

Emerin is a nuclear membrane-anchored protein which is absent or mutated in patients affected by Emery-Dreifuss muscular dystrophy. In this study, we induced apoptosis in cultured mouse myoblasts to evaluate emerin fate during the nuclear destabilization involved in programmed cell death. Emerin proteolysis was observed in myocytes during the apoptotic process. Myoblast apoptosis and emerin degradation were associated with chromatin compaction and detachment from the nuclear lamina, as detected by electron microscopy. In vivo specific inhibition of caspase 3 or caspase 6 activity completely abolished emerin proteolysis. These results show that the process of programmed cell death in muscle cells leads to emerin proteolysis, which appears to be related to caspase 6 activation and to cleavage of other nuclear envelope proteins, that share sequence homologies or functional features with emerin.     

Proliferating ability,morphological development and acetylcholinesterase activity of the neural tube cells in early chick embryos

Summary Using ³H-thymidine autoradiography and AChE histochemistry at the electron microscopic level on the same sections, the interrelationships between loss of proliferating ability, morphological development and increase of AChE activity during the course of differentiation of the neural tube cells were investigated in early chick embryos. The neural tube wall consisted of spindle-shaped cells with no AChE activity, weakly positive spindle-shaped cells showing AChE activity in the cisternae of the nuclear envelope and in a few short profiles of r-ER, moderately positive spindle-shaped cells showing AChE activity in the nuclear envelope and in a moderate number of r-ER profiles and intensely positive large round cells showing AChE activity in the nuclear envelope and in a large number of r-ER profiles. Nuclei of the AChE-negative, weakly positive and moderately positive cells were located in the ependymal layer (matrix). The AChE-intensely positive cells were in the mantle layer. The AChE-negative and weakly positive cells were capable of proliferation and were regarded as undifferentiated neuroepithelial cells. In contrast, the moderately positive and intensely positive cells were no longer capable of proliferation and were considered to be neurons. These findings indicate that the r-ER increases rapidly in amount and volume in newly formed neurons soon after their final cell division, and that AChE increases in the neurons in parallel to the development of the r-ER.     

Microtubule Destabilization Paves the Way to Parkinson’s Disease

Microtubules are dynamic structures normally associated to the cell division, during which they form the mitotic spindle, as well as to the initial phases of specification and polarization of various cell types, including neurons. Although microtubules could have a role in the death of many cells and tissues, the microtubule-based degenerative mechanisms have been poorly investigated; nevertheless, during the last two decades, many clues have been accumulated suggesting the importance of the microtubule system during neurodegeneration. Thus, the aim of this review is to analyse how the changes of the microtubule cytoskeleton, in terms of organization and dynamics, as well as the failure of the microtubule-dependent neuronal processes, as axonal transport, may play a pivotal role in the chain of events leading to Parkinson’s disease. Last but not least, since disease-modifying or neuroprotective strategies are a clinical priority in Parkinson’s disease, we will also present the hints about the concrete possibility of a microtubule-targeted therapy, which would have the potentiality to block the running degenerative events and to prompt the regeneration of the lost tissues.     

Cell death of asynaptic neurons in regenerating spinal cord

The weakly electric fish Sternarchus albifrons possesses a unique class of asynaptic neurons, the electromotor neurons, whose axons constitute the electric organ. The cell bodies of origin of the electrocyte axons are located in the spinal cord. Both spinal cord and electromotor neurons ( electrocytes ) regenerate after amputation of the tail. Sternarchus spinal cords which have regenerated for 1 or more years show a progression in number of perikarya of electromotor neurons along the rostro-caudal axis. The most recently regenerated region of the cord is at the caudal end, which consists of a tube of ependyma. Progressing rostrally along regenerated spinal cord from the caudal end, numerous cells are generated and large numbers of electromotor neurons differentiate. The maximum number of electromotor neurons per transverse section of regenerated cord is five times higher than in normal mature cord. Rostral to this, the number of electromotor neurons decreases gradually to the normal number near the transition zone (the border with unregenerated cord). As the more rostral regenerated cord has presumably had a longer period of regeneration, we conclude that excess numbers of electromotor neurons are generated initially, and that subsequently the number of these neurons is decreased by cell death. This conclusion is supported by the fact that younger regenerates (2-4 months) have larger-than-normal numbers of perikarya of electromotor neurons extending up to the transition zone (Anderson and Waxman , 1981). No evidence of migration or depletion of electromotor neurons from unregenerated cord rostral to the amputation has been observed. Since the axons of the electromotor neurons in Sternarchus do not normally form any synapses, this study provides evidence that factors other than synaptic competition must be responsible for determining cell death during regeneration of these spinal neurons.     

Activation of the caspase-3 apoptotic cascade in traumatic spinal cord injury.

Traumatic spinal cord injury often results in complete loss of voluntary motor and sensory function below the site of injury. The long-term neurological deficits after spinal cord trauma may be due in part to widespread apoptosis of neurons and oligodendroglia in regions distant from and relatively unaffected by the initial injury. The caspase family of cysteine proteases regulates the execution of the mammalian apoptotic cell death program. Caspase-3 cleaves several essential downstream substrates involved in the expression of the apoptotic phenotype in vitro, including gelsolin, PAK2, fodrin, nuclear lamins and the inhibitory subunit of DNA fragmentation factor. Caspase-3 activation in vitro can be triggered by upstream events, leading to the release of cytochrome c from the mitochondria and the subsequent transactivation of procaspase-9 by Apaf-1. We report here that these upstream and downstream components of the caspase-3 apoptotic pathway are activated after traumatic spinal cord injury in rats, and occur early in neurons in the injury site and hours to days later in oligodendroglia adjacent to and distant from the injury site. Given these findings, targeting the upstream events of the caspase-3 cascade has therapeutic potential in the treatment of acute traumatic injury to the spinal cord.     

Specific association of c-Jun-like immunoreactivity but not c-Jun p39 with normal and induced programmed cell death in the chick embryo

We have examined c-Jun protein expression by immunocytochemistry in normal and pathologically induced cell death by focusing primarily on the developing neuromuscular system of the chick embryo. Several commercially available antibodies against c-Jun were used in combination with the TUNEL technique or propidium iodide staining for detection of cells undergoing programmed cell death (PCD). Among these, a rabbit polyclonal antibody raised against the amino acids 91-105 mapping to the amino terminal domain of mouse c-Jun p39 (c-Jun/sc45) transiently immunostained the cytoplasm of dying spinal cord motoneurons at a time coincident with naturally occurring motoneuron death. Late apoptotic bodies were devoid of c-Jun/sc45 immunoreactivity. A monoclonal antibody directed against a region corresponding to the amino acids 26-175 of c-Jun p39 (c-Jun/mAB) did not specifically immunostain dying neurons, but, rather, showed nuclear immunolabeling in almost all healthy motoneurons. Experimentally induced programmed death of motoneurons by means of early limb bud ablation, axotomy, or in ovo injection of the neurotoxin beta-bungarotoxin increased the number of dying cells showing positive c-Jun/sc45 immunoreactivity. Immunoelectron microscopy with c-Jun/sc45 antibody showed that the signal was present in the cytoplasm without a specific association with organelles, and was also present in large lysosome-like dense bodies inside neuritic profiles. Similar findings were obtained in different types of cells undergoing normal or experimentally induced PCD. These include dorsal root ganglion neurons, Schwann cells, muscle cells, neural tube and neural crest cells during the earliest stages of spinal cord development, and interdigital mesenchymal cells of hindlimbs. In all these cases, cells showed morphological and histochemical characteristics of apoptotic-like PCD. By contrast, motoneurons undergoing necrotic cell death induced by the excitotoxin N-methyl-D-aspartate did not show detectable c-Jun/sc45 immunoreactivity, although they displayed an increase in nuclear c-Jun/mAB immunostaining. In Western blot analysis of spinal cord extracts, c-Jun/sc45 antibody weakly detected a 39-kD band, corresponding to c-Jun, and more strongly detected two additional bands of 66 and 45 kD which followed developmental changes coincident with naturally occurring or experimentally stimulated apoptotic motoneuron death. By contrast, c-Jun/mAB only recognized a single p39 band as expected for c-Jun, and did not display changes associated with neuronal apoptosis. From these data, we conclude that the c-Jun/sc45 antibody recognizes apoptosis-related proteins associated with the early stages of morphological PCD in a variety of neuronal and non-neuronal cells, and that c-Jun/sc45 is a reliable marker for a variety of developing cells undergoing programmed cell death.     

Identification of tyrosine-phosphorylated proteins associated with the nuclear envelope.

The nuclear envelope separates the nucleoplasm from the rest of the cell. Throughout the cell cycle, its structural integrity is controlled by reversible protein phosphorylation. Whereas its phosphorylation-dependent disassembly during mitosis is well characterized, little is known about phosphorylation events at this structure during interphase. The few characterized examples cover protein phosphorylation at serine and threonine residues, but not tyrosine phosphorylation at the nuclear envelope. Here, we demonstrate that tyrosine phosphorylation and dephosphorylation occur at the nuclear envelope of intact Neuro2a mouse neuroblastoma cells. Tyrosine kinase and phosphatase activities remain associated with purified nuclear envelopes. A similar pattern of tyrosine-phosphorylated nuclear envelope proteins suggests that the same tyrosine kinases act at the nuclear envelope of intact cells and at the purified nuclear envelope. We have also identified eight tyrosine-phosphorylated nuclear envelope proteins by 2D BAC/SDS/PAGE, immunoblotting with phosphotyrosine-specific antibodies, tryptic in-gel digestion, and MS analysis of tryptic peptides. These proteins are the lamina proteins lamin A, lamin B1, and lamin B2, the inner nuclear membrane protein LAP2beta, the heat shock protein hsc70, and the DNA/RNA-binding proteins PSF, hypothetical 16-kDa protein, and NonO, which copurify with the nuclear envelope.     

Acetylcholinesterase distribution in chick spinal cord cultures

Summary Explants of 10–12 day chick embryo spinal cord were cultured by coverslip-roller tube method for 3–80 days. The cellular and subcellular localization of acetylcholinesterase activity in cultured neurons was studied by the thiocholine techniques of Karnovsky and Roots and Lewis and Shute.At the light microscopic level, acetylcholinesterase was demonstrated in the neurons of both ventral and dorsal horn regions. Occasionally neurons migrated in the outgrowth zone exhibited strong intracellular activity.At the electron microscopic level, acetylcholinesterase activity was found in the nuclear envelope, granular endoplasmic reticulum and the Golgi apparatus of the neurons. No enzyme reaction was detected in the glial cell cytoplasm.     

Nicotine protects against arachidonic-acid-induced caspase activation, cytochrome c release and apoptosis of cultured spinal cord neurons

Hydrolysis of membrane phospholipids of spinal cord neurons is one of the first events initiated in spinal cord trauma. In this process, free fatty acids, and in particular arachidonic acid, are released. Exposure of spinal cord neurons to free arachidonic acid can compromise cell survival and initiate apoptotic cell death. In order to determine potential mechanisms of apoptosis induced by arachidonic acid, activation of caspases -3, -8, and -9, as well as the release of cytochrome c into the cytoplasm were measured in cultured spinal cord neurons exposed to 10 microM of this fatty acid. In addition, because nicotine can exert a variety of neuroprotective effects, we hypothesized that it can prevent arachidonic acid induced apoptosis of spinal cord neurons. To study this hypothesis, spinal cord neurons were pretreated with nicotine (10 microM for 2 h) before arachidonic acid exposure and caspase activation as well as markers of apoptotic cell death were studied. Treatment of spinal cord neurons with arachidonic acid for up to 24 h significantly increased cytoplasmic levels of cytochrome c, induced caspase activation and induced DNA laddering, a hallmark of apoptotic cell death. Nicotine pretreatment markedly attenuated all these effects. In addition, antagonist studies suggest that the alpha7 nicotinic receptor is primarily responsible for these anti-apoptotic effects of nicotine. These results indicate that nicotine can exert potent neuroprotective effects by inhibiting arachidonic acid induced apoptotic cascades of spinal cord neurons.     

Abortive synaptogenesis as a factor in the inner hair cell degeneration in the bronx waltzer (bv) mutant mouse

The bronx waltzer (vb) mutation in the mouse results in the degeneration of most but not all of the primary auditory receptors, the inner hair cells, and their afferent neurons. We analyzed the ultrastructure of 94 inner hair cells in the intact postnatal mutant mouse and in neonatal cochleas in culture to understand the pathogenesis of hair cell death and to detect factors that may prevent it. The vb spiral neurons of the bronx waltzer display two distinctive features: some of them continue to divide mitotically for at least seven postnatal days, and the type I radial fibers that innervate inner hair cells display a deficiency in immunoexpression of GAD. The growing endings of spiral neurons converge around the inner hair cells or, in their absence, invade the outer hair cell region. Their profuse sprouting among inner spiral sulcus cells contributes to the characteristic ultrastructural picture of the bv cochlea. During the first three days after birth, 40% of the inner hair cells appear normal and innervated, 40% are mostly denervated and degenerating, and 20% are immature, with minimal or no neuronal appositions. However, in mutants 6 days and older only a few inner hair cells survive, and these show either normal or superfluous afferent innervation and axosomatic GABAergic efferent innervation. Degeneration of inner hair cells begins with a distention of the nuclear envelope and the ribosomal endoplasmic reticulum. The outer nuclear membrane eventually breaks, and exudate fills the cell interior. The cellular edema leads to cell death. We propose that success or failure in synaptic acquisition is a decisive factor in the survival or decline of the mutant inner hair cells. We also suggest that the developmental delay in maturation of the spiral ganglion neurons (type I) and the failure in their synaptogenesis may be caused by an impairment in neurotrophin (NT3/BDNF) synthesis by their mutant receptor cells.     

Cell-Adhesion to Crystal Surfaces: Adhesion-Induced Physiological Cell Death

Cultured epithelial cells interact massively, rapidly and stereospecifically with the {011} faces of calcium (R,R)-tartrate tetrahydrate crystals. It was suggested that the massive rapid adhesion represents an exaggerated and isolated form of the first initial events in the attachment of cultured cells to conventional tissue culture surfaces (Hanein, et al., Cells and Materials, 5, 197–210: 1995). Attachment is however not followed by normal cell spreading and development of focal adhesions, but results in massive cell death. In this study, the fate of the crystal-bound cells was characterized by electron microscopy, flow cytometry and microscopic morphometry and was found to display the characteristics of physiological cell death. We show that the direct interaction with the highly homogenous and repetitive {011} faces per se does not trigger the transduction of lethal transmembrane signals. We suggest that the excessive direct interactions between the cell membrane and the crystal. by impairing cell motion, prevent the evolution of RGD-dependent cell adhesion. This implies that the deprivation of proper extracellular matrix (ECM)-receptor contacts of substrate-attached epithelial cells eventually triggers physiological cell death.     

Impairment of the mitochondrial respiratory enzyme activity triggers sequential activation of apoptosis-inducing factor-dependent and caspase-dependent signaling pathways to induce apoptosis after spinal cord injury

The mitochondrion participates in caspase-independent or caspase-dependent apoptotic pathways through the release of apoptosis-inducing factor or cytochrome c. Whether both mitochondrial apoptotic cascades are triggered in the injured spinal cord remains unknown. Here, we demonstrated that neurons, astrocytes and microglia in spinal segments proximal to a complete spinal cord transection underwent two phases of apoptotic cell death. The early phase of high-molecular weight (HMW) DNA fragmentation was associated with nuclear translocation of apoptosis-inducing factor, reduction in mitochondrial respiratory chain enzyme activity and decrease in cellular ATP concentration. The delayed phase of low-molecular weight (LMW) DNA fragmentation was accompanied by cytosolic release of cytochrome c , activation of caspases 9 and 3, and resumption of mitochondrial respiratory functions and ATP contents. Microinfusion of coenzyme Q₁₀, an electron carrier in mitochondrial respiratory chain, into the epicenter of the transected spinal cord attenuated both phases of induced apoptosis, and reversed the elicited mitochondrial dysfunction, bioenergetic failure, and activation of apoptosis-inducing factor, cytochrome c , or caspases 9 and 3. We conclude that mitochondrial dysfunction after spinal cord transection represents the initiating cellular events that trigger the sequential activation of apoptosis-inducing factor-dependent and caspase-dependent signaling cascades, leading to apoptotic cell death in the injured spinal cord.     

Surviving Drosophila eye development

During eye development, cell death interplays dynamically with events of differentiation to achieve the remarkably patterned structure of the fly compound eye. Mutations in genes that affect the normal developmental process can lead to excessive death of progenitor cells, or, alternatively, to the differentiation of supernumerary neurons, pigment and cone cells due to survival of cells that would normally be eliminated. These data reveal that eye development contains cell selection processes: only certain cells are selected to undergo differentiation, and supernumerary cells are actively eliminated by cell death pathways to achieve the highly ordered lattice of the eye. The final number of cells that comprise the eye is controlled through a balance of cell proliferation with proper cell differentiation and removal by cell death.