When dying is not the end: Apoptotic caspases as drivers of proliferation.

Caspases are well known for their role as executioners of apoptosis. However, recent studies have revealed that these lethal enzymes also have important mitogenic functions. Caspases can promote proliferation through autonomous regulation of the cell cycle, as well as by induction of secreted signals, which have a profound impact in neighboring tissues.

Spreading the word: non-autonomous effects of apoptosis during development, regeneration and disease.

Apoptosis, in contrast to other forms of cell death such as necrosis, was originally regarded as a 'silent' mechanism of cell elimination designed to degrade the contents of doomed cells. However, during the past decade it has become clear that apoptotic cells can produce diverse signals that have a profound impact on neighboring cells and tissues. For example, apoptotic cells can release factors that influence the proliferation and survival of adjacent tissues.

The benefits of aging: cellular senescence in normal development.

Senescence is a form of cellular aging that limits the proliferative capacity of cells. Senescence can be triggered by different stress stimuli, such as DNA damage or oncogene activation. Two recent articles published in Cell have uncovered an unexpected role for cellular senescence during development, as a process that contributes to remodeling and patterning of the embryo.

Apoptotic cells can induce non-autonomous apoptosis through the TNF pathway.

Apoptotic cells can produce signals to instruct cells in their local environment, including ones that stimulate engulfment and proliferation. We identified a novel mode of communication by which apoptotic cells induce additional apoptosis in the same tissue. Strong induction of apoptosis in one compartment of the Drosophila wing disc causes apoptosis of cells in the other compartment, indicating that dying cells can release long-range death factors.

Mitogenic signaling from apoptotic cells in Drosophila.

Apoptotic cells of Drosophila not only activate caspases, but also are able to secrete developmental signals like Hedgehog (Hh), Decapentaplegic (Dpp) and Wingless (Wg) before dying. Since Dpp and Wg are secreted in growing tissues and behave as growth factors, it was proposed that they play a role in compensatory proliferation, the process by which a growing blastema can restore normal size after massive apoptosis. We discuss recent results showing that there is normal compensatory proliferation in the absence of Dpp/Wg signaling, thus indicating it has no significant role in the process.

A tumor-suppressing mechanism in Drosophila involving cell competition and the Hippo pathway.

Mutant larvae for the Drosophila gene lethal giant larva (lgl) develop neoplastic tumors in imaginal discs. However, lgl mutant clones do not form tumors when surrounded by wild-type tissue, suggesting the existence of a tumor-suppressing mechanism. We have investigated the tumorigenic potential of lgl mutant cells by generating wing compartments that are entirely mutant for lgl and also inducing clones of various genetic combinations of lgl(-) cells.

Apoptosis in Drosophila: compensatory proliferation and undead cells.

Apoptosis (programmed cell death) is a conserved process in all animals, used to eliminate damaged or unwanted cells after stress events or during normal development to sculpt larval or adult structures. In Drosophila, it is known that stress events such as irradiation or heat shock give rise to high apoptotic levels which remove more than 50% of cells in imaginal discs. However, the surviving cells are able to restore normal size and pattern, indicating that they undergo additional proliferation.

The role of Dpp and Wg in compensatory proliferation and in the formation of hyperplastic overgrowths caused by apoptotic cells in the Drosophila wing disc.

Non-lethal stress treatments (X-radiation or heat shock) administered to Drosophila imaginal discs induce massive apoptosis, which may eliminate more that 50% of the cells. Yet the discs are able to recover to form final structures of normal size and pattern. Thus, the surviving cells have to undergo additional proliferation to compensate for the cell loss.

Dpp of posterior origin patterns the proximal region of the wing.

The decapentaplegic (dpp) gene encodes a long-range morphogen that plays a key role in the patterning of the wing imaginal disc of Drosophila (Nellen, D., Burke, R., Struhl, G.

Dpp signaling and the induction of neoplastic tumors by caspase-inhibited apoptotic cells in Drosophila.

In Drosophila, stresses such as x-irradiation or severe heat shock can cause most epidermal cells to die by apoptosis. Yet, the remaining cells recover from such assaults and form normal adult structures, indicating that they undergo extra growth to replace the lost cells. Recent studies of cells in which the cell death pathway is blocked by expression of the caspase inhibitor P35 have raised the possibility that dying cells normally regulate this compensatory growth by serving as transient sources of mitogenic signals.

Caspase inhibition during apoptosis causes abnormal signalling and developmental aberrations in Drosophila.

Programmed cell death or apoptosis plays an important role in the development of multicellular organisms and can also be induced by various stress events. In the Drosophila wing imaginal disc there is little apoptosis in normal development but X-rays can induce high apoptotic levels, which eliminate a large fraction of the disc cells. Nevertheless, irradiated discs form adult patterns of normal size, indicating the existence of compensatory mechanisms.

The brinker gradient controls wing growth in Drosophila.

The Decapentaplegic (Dpp) morphogen gradient controls growth and patterning in the Drosophila appendages. There is recent evidence indicating that the Dpp gradient is converted into an inverse gradient of activity of the gene brinker (brk), which encodes a transcriptional repressor and is negatively regulated by the Dpp pathway. We have studied how alterations in the Brk gradient affect the growth of the wing disc.