114 



Cellular Structure and Activity 



that some cells retain or regain the ability to 

 synthesize specific compounds that are essen- 

 tial for mitosis, while other tissues remain 

 unable to do so. 



Sometimes differentiation is connected 

 with a permanent loss of mitotic activity. In 

 vertebrates this applies to nerve cells and 

 striated muscle. In some invertebrates the 

 development of the entire organism or of 

 certain organs is a closed system involving 

 a specific and constant number of cell divi- 

 sions. When morphogenesis is complete all 

 cells have lost the ability to divide. 



An important aspect of mitogenesis is the 

 "latent period." Whether in tissue culture or 

 in vivo, no matter what the stimulus, there 

 is invariably a period of many hours be- 

 tween application of the stimulus and ap- 

 pearance of the first mitosis. In tissue culture 

 it lasts from 20 to 24 hours (Fischer, '46). 

 It depends to some extent on the type of 

 medium (Jacoby, '49). In explants of liver 

 it is not the same in different types of cells 

 (Abercrombie and Harkness, '51). It is gen- 

 erally longer than the interphase imder op- 

 timal conditions. Growth factors act during 

 this time and once mitosis is under way they 

 are no longer required until the next ante- 

 phase (Jacoby, '37). No doubt mitotic stimu- 

 lation produces some essential changes in 

 the cytoplasm, as is borne out by the many 

 observations of synchronous division of nu- 

 clei in the same cell or in cells connected 

 by cytoplasmic bridges. Whatever the nature 

 of this change it does not go beyond the cell 

 membrane. 



In other cells synchronous divisions are 

 most likely the result of an inherent rhythm 

 of mitosis with a fixed length of the various 

 phases characterizing the particular type 

 of cell (spermatocytes of insects, early cleav- 

 age). 



The rate at which the number of cells 

 increases in a tissue depends on the time for 

 mitosis, the length of the interphase and the 

 rate of removal of cells from the proliferating 

 population by death or differentiation. The 

 sum of mitotic time and interphase has been 

 called generation time. Mitotic time and 

 length of interphase for some cells can be 

 determined directly by observation (eggs, 

 tissue culture). In the intact animal the 

 time for mitosis has been determined for 

 several tissues by making use of the fact 

 that moderate doses of x-rays inhibit the ante- 

 phase so that no new cells enter mitosis, but 

 those in division continue normally (Knowl- 

 ton and Widner, '50; Widner et al., '51). 

 From the mitotic index (number of dividing 



cells/number of interphases) and the mitotic 

 time the average length of interphase can be 

 calculated (Table 4). 



The shortest generation time is found in 

 early cleavage. Probably the shortest on 

 record was reported for early cleavage of 

 Drosophila (Huettner, '33). A short inter- 

 phase is characteristic also for certain em- 

 bryonic cells such as the neuroblasts in the 

 grasshopper (Carlson and Hollaender, '48). 



In vertebrates the average mitotic time is 

 remarkably similar from one tissue to an- 

 other. Even in embryonic cells in tissue cul- 

 ture and in various tumors the time for 

 mitosis is about the same. The average length 

 of interphase, however, is very variable. As 

 shown in tissue culture it differs even in 

 daughter cells (Jacoby, '49; Fell and Hughes, 

 '49). In other cells, for instance in spermato- 

 cytes (Ris, '49) or in cleaving eggs, mitotic 

 time and interphase may be remarkably con- 

 stant under the same conditions. 



The generation time is determined by in- 

 trinsic factors and by external conditions. 

 In the eggs of sea urchins (Moore, '33), am- 

 phibians (Porter, '42) and fishes (Moenk- 

 haus, '04), the rate of cleavage is specific for 

 a species and is determined by the cyto- 

 plasm. In later cleavage blastomeres may 

 have different rates, specific for each cell and 

 independent of the size of the cells (Chen 

 and Pai, '49). 



Both mitotic time and interphase are in- 

 fluenced by environmental factors, for in- 

 stance, temperature (Barber, '39), pH, con- 

 centration of embryo extract in tissue cul- 

 ture (Jacoby, '37), tonicity of the medium 

 (Cornman, '43), and the presence of certain 

 ions (Moellendorff, '38) and hormones (Bul- 

 lough, '52). The mitotic index has often been 

 used as a measure for the proliferative ac- 

 tivity of a tissue. To draw any conclusion, 

 however, more than jvist the index must be 

 known. The relationship of mitotic time and 

 interphase to the mitotic index under vari- 

 ous conditions was discussed by Hoffmann 

 ('49). 



We may conclude that many factors in- 

 fluence in one way or another the number 

 of cells in division or change the mitotic 

 time or length of interphase and in a few 

 cases we have some information on the mech- 

 anisms of these effects. Other factors are 

 known that are truly mitogenetic, that induce 

 cells to enter mitosis that would not normally 

 divide, even though energy sources and 

 building blocks may be available. So far 

 little is known of how this change in cells 

 is brought about. 



