The sorting of chromosomes that takes place during meiosis is a remarkable feat of intracellular bookkeeping. In humans, each meiosis requires that the starting cell keep track of 92 chromatids (46 chromosomes, each of which has duplicated), distributing one complete set of each type of autosome to each of the four haploid progeny. Not surprisingly, mistakes can occur in allocating the chromosomes during this elaborate process. Mistakes are especially common in human female meiosis, which arrests for years after diplotene: meiosis I is completed only at ovulation, and meiosis II only after the egg is fertilized. Indeed, such chromosome segregation errors during egg development are the most common cause of both spontaneous abortion (miscarriage) and mental retardation in humans.
When homologs fail to separate properly—a phenomenon called nondisjunction—the result is that some of the resulting haploid gametes lack a particular chromosome, while others have more than one copy of it. Upon fertilization, these gametes form abnormal embryos, most of which die. Some survive, however. Down syndrome in humans, for example, which is the leading cause of mental retardation, is caused by an extra copy of chromosome 21, usually resulting from nondisjunction during meiosis I in the female ovary. Segregation errors during meiosis I increase greatly with advancing maternal age.
Haploid gametes are produced by meiosis, in which a diploid nucleus undergoes two successive cell divisions after one round of DNA replication. Meiosis is dominated by a prolonged prophase. At the start of prophase, the chromosomes have replicated and consist of two tightly joined sister chromatids. Homologous chromosomes then pair up and become progressively more closely juxtaposed as prophase proceeds. The tightly aligned homologs undergo genetic recombination, forming crossovers that help hold each pair of homologs together during metaphase I. Meiosis-specific, kinetochore-associated proteins help ensure that both sister chromatids in a homolog attach to the same spindle pole; other kinetochore-associated proteins ensure that the homologs remain connected at their centromeres during anaphase I, so that homologs rather than sister chromatids are segregated in meiosis I. After meiosis I, meiosis II follows rapidly, without DNA replication, in a process that resembles mitosis, in that sister chromatids are pulled apart at anaphase.
A fertilized mouse egg and a fertilized human egg are similar in size, yet they produce animals of very different sizes. What factors in the control of cell behavior in humans and mice are responsible for these size differences? The same fundamental question can be asked for each organ and tissue in an animal’s body. What factors determine the length of an elephant’s trunk or the size of its brain or its liver? These questions are largely unanswered, but it is nevertheless possible to say what the ingredients of an answer must be.
The size of an organ or organism depends on its total cell mass, which depends on both the total number of cells and their size. Cell number, in turn, depends on the amounts of cell division and cell death. Organ and body size are therefore determined by three fundamental processes: cell growth, cell division, and cell survival. Each is tightly regulated—both by intracellular programs and by extracellular signal molecules that control these programs.
The extracellular signal molecules that regulate cell growth, division, and survival are generally soluble secreted proteins, proteins bound to the surface of cells, or components of the extracellular matrix. They can be divided operationally into three major classes: 1.
Mitogens, which stimulate cell division, primarily by triggering a wave of G1/S-Cdk activity that relieves intracellular negative controls that otherwise block progress through the cell cycle.
2.
Growth factors, which stimulate cell growth (an increase in cell mass) by promoting the synthesis of proteins and other macromolecules and by inhibiting their degradation.
3.
Survival factors, which promote cell survival by suppressing the form of programmed cell death known as apoptosis.