Cell death is prominent in gametogenesis and shapes and sculpts embryos. In nonmammalian embryos one sees little or no cell death prior to the maternal-zygotic transition, but, in mammalian embryos, characteristic deaths of one or two cells occur at the end of compaction and are apparently necessary for the separation of the trophoblast from the inner cell mass. Considerable sculpting of the embryo occurs by cell deaths during organogenesis, and appropriate cell numbers, especially in the CNS and in the immune system, are generated by massive overproduction of cells and selection of a few, with death of the rest. The timing, identity, and genetic control of specific cells that die have been well documented in Caenorhabditis, but in other embryos the stochastic nature of the deaths limit our ability to do more than identify the regions in which cells will die. Complete disruption of the cell death machinery can be lethal, but many mutations of the regulatory machinery yield only modest or no phenotypes, indicating substantial redundancy and compensation of regulatory mechanisms. Most of the deaths are apoptotic and are identified by techniques used to recognize apoptosis, but techniques identifying lysosomes (whether in dying or involuting cells or in the phagocytes that invade the tissue) also reveal patterns of cell death. Aberrant cell deaths that produce known phenotypes are typically localized, indicating that the mechanism of activating a programmed death in a specific region, rather than the mechanism of death, is aberrant. These results lead us to conclude that we need to know much more about the conversations among cells that lead cells to commit suicide. KEY WORDS: apoptosis, autophagy, caspase, necrosis, programmed cell death Cell death in development -a historical perspectiveCell death is a fundamental aspect of normal embryonic differentiation, morphogenesis, and teratogenesis, as well as of many diseases. Our understanding of these facts stems from considerable research as well as from old and very recent information. The great 19 th century embryologist, Carl Vogt, saw cell death in embryos as early as 1842 (Vogt, 1842), and by 1885 Walter Flemming documented the obvious, that loss of tadpole structures during metamorphosis resulted from cell death (Flemming, 1885). Throughout the early 20 th Century, many researchers examined the death of larval tissues in metamorphosing insects. By mid-century, Levi-Montalcini and Hamburger had demonstrated that the same number of neurons were born in each sympathetic or sensory ganglion, whether or not the ganglion supported a limb (Hamburger and Levi-Montalcini, 1949). Subsequently, in segments of the spinal cord that did not support a limb, many of the neurons died, resulting in much smaller ganglia (Hamburger and Levi-Montalcini, 1949). These investigations ultimately led to the discovery of nerve Int. J. Dev. Biol. 59: 11-22 (2015) doi: 10.1387/ijdb.150220zz Abbreviations used in this paper: CHX, cycloheximide; CNS, central nervous system; ICM, in...

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Cyclin-dependent kinase 5 (Cdk5) is similar to other Cdks but is activated during cell differentiation and cell death rather than cell division. Since activation of Cdk5 has been reported in many situations leading to cell death, we attempted to determine if it was required for any form of cell death. We found that Cdk5 is activated during apoptotic deaths and that the activation can be detected even when the cells continue to secondary necrosis. This activation can occur in the absence of Bim, calpain, or neutral cathepsins. The kinase is typically activated by p25, derived from p35 by calpain-mediated cleavage, but inhibition of calpain does not affect cell death or the activation of Cdk5. Likewise, RNAi-forced suppression of the synthesis of Cdk5 does not affect the incidence or kinetics of cell death. We conclude that Cdk5 is activated as a consequence of metabolic changes that are common to many forms of cell death. Thus its activation suggests processes during cell death that will be interesting or important to understand, but activation of Cdk5 is not necessary for cells to die.

Mammalian development is dependent on an intricate orchestration of cell proliferation and death. Deregulation in the levels, localization, and type of cell death can lead to disease and even death of the developing embryo. The mechanisms involved in such deregulation are many; alterations and or manipulations of these can aid in the detection, prevention and possible treatments of any effects this de-regulation may have. Here we describe how cell death can be detected during mammalian development, using diverse staining and microscopy methods, while taking advantage of the advancements in cell death mechanisms, derived from biochemical and teratological studies in the field.