304 CELLS, TISSUES, AND ORGANISMS 



even dissolve it away, and by this action preserve the intimacy of con- 

 tact between blastema and apical epidermis. We like to entertain the 

 possibility that the epidermal secretion reflects the histolytic function 

 of the epithelium. It may be that proteolytic enzymes are discharged 

 from the epidermal cells of the regenerate into the intercellular spaces 

 and subepidermal regions. In the latter case, the secretion may con- 

 tribute to the widespread histolysis of old tissues of the stump that 

 characterizes the early regenerate stages and results in morphological 

 dedifferentiation of adult tissue and the formation of the blastema 

 ( Orechowitsch and Bromley, 1934). Jefimoff (1933) and Polezaiev 

 and Faworina (1935), among others, have already attributed a role 

 of the epithelium to initiation of proteolysis. Perhaps the epithelium is 

 itself one of the agents of tissue breakdown and contributes lytic en- 

 zymes to the blastema as well as to its fluidy interspaces. This seems 

 a reasonable possibility in the light of the fact that proteolytic activity 

 has been demonstrated a number of times in the epidermis of higher 

 forms (see, for example. Wells and Babcock, 1953; Rothman, 1954). 

 There is one other possible use of epidermal secretion into the blas- 

 tema. It may serve to attract mesenchymatous cells beneath the epi- 

 thelium to form the blastema of regeneration. 



The extent of the epidermal response to events of regeneration 

 may depend on many factors, one of which is hormonal. For example, 

 Schmidt (1958a) has observed that thyroidectomy causes the epi- 

 dermis of the adult newt to grow faster and to form an apical cap 

 sooner. Moreover, the epidermis protrudes more deeply than ordinarily 

 into wound tissues. 



Invasion of the epidermis by nerve fibers 



What initiates epidermal activity and maintains its high state, es- 

 pecially during the formative stages of regeneration, is not known. 

 There is, of course, the excitation of freshly wounded tissues, but 

 within a few days this stimulus should subside as fibrocellular scar 

 tissue is laid down. Yet the excitement appears to become intense ten 

 days or two weeks after wounding, and the epithelium becomes thick 

 and most reactive. It is possible that, in addition to the primary 

 response to wounding, another response, or perhaps a continuation of 

 the primary one, is called forth by underlying regenerative events. In 

 recent years the theory has been advanced that the nerves of the 

 regenerate initiate and maintain activity in the epidermis important for 

 regeneration. The theory arose from the demonstration by one of us 

 that the epithelium of the regenerating forelimb of the newt is invaded 

 by many naked nerve fibers which wander freely among the epidermal 

 cells ( Singer, 1949, 1949a ) . The incursion by nerve fibers was affirmed 



