526 MOLECULAR MECHANISMS OF DIFFERENTIATION 5 



(Vogt, 1947). This suggests that a decrease in the rate of proHferation leads to a 

 divergent course of differentiation. 



Fascinating objects for the study of differentiation in general (Raper, 1956) 

 and of the relation of differentiation and proliferation in particular are the slime 

 molds. Recent studies (Bonner and Frascella, 1952; Sussman, 1956) have show^n 

 that the late manifestations of differentiation, like formation of the stalk wall, or 

 of the fruiting body occur after the cessation of proliferation. However, histoche- 

 mical indices of differentiation like absence or presence of PAS staining material 

 can be detected while proliferative activity still occurs (Bonner, Chiquoine, and 

 Kolderie, 1955). From the latter study it is also apparent that the process of differ- 

 entiation in slime molds can be reversed during a remarkably long period of 

 development. 



Quantitative data on the relationship between proliferation and differentiation 

 have become available in the course of a systematic survey of the transition of the 

 vuidifferentiated mesoderm into fully differentiated muscle cells (Herrmann, 1952). 

 The rate of proliferation during early mesodermal differentiation may be repre- 

 sented by measurements of protein nitrogen, RNA, and DNA, in somites of the 

 chick embryo. Before the 24-somite stage the values found for these parameters 

 double in 10-18 h. and by the time the full complement of somites is formed 

 doubling time has increased to 24 h. (Herrmann, Schneider, Neukom and Moore, 

 1 951), About the same value is still found for the growth rate of the total leg muscle 

 from the 8th to the i ith day of development (Herrmann, White and Cooper, 1957). 

 Data on the weight of the entire leg of the chick embryo from the 5th to the i ith 

 day of development show only a slight increase in doubling time from 19-26 h. 

 and for the DNA content of the leg a varying value of 25-33 h. is found for a 

 100% increase (Nowinski and Yushok, 1953). After the nth day the rate of 

 accumulation of the dry weight and the DNA of the leg muscle begins to diminish 

 and a sharp drop occurs after the 14th day. DNA accumulation comes practically 

 to a standstill after the i8th day. On the other hand, beginning at about the 12th 

 day of development the proteins, actomyosin and collagen, differentiation prod- 

 ucts of the myoblast and the fibroblast respectively, become detectable with 

 analytical methods and the total quantity of these proteins continues to increase 

 at a high rate. For collagen the doubling time remains 24 h. up to the i6th day 

 and diminishes rapidly afterwards, reaching the rate of the overall protein accumu- 

 lation. In the case of actomyosin the doubling time is somewhat less than 24 h. on 

 the 1 2th day but this rate decreases less abruptly than in case of collagen and even 

 at one month after hatching actomyosin accumulates faster than the remaining 

 bulk of cellular proteins (Herrmann and Barry, 1955; Csapo and Herrmann, 1951 ; 

 Herrmann, White and Cooper, 1957). 



These results seem to indicate that even in expressing the degree of differentiation 

 as accumulation of individual specific proteins, at least in the case of muscle, a 

 certain complementarity of proliferation and differentiation can be observed. It is 

 rather remarkable, however, that the rate at which the specific proteins continue 

 to accumulate after cell proliferation diminishes, is of the same order of magnitude 

 as the accumulation of the bulk of proteins during the more rapid phases of 

 proliferation. Considering the three alternative relations between total protein 



