Abstract
In 1901 T.H. Morgan proposed in "Regeneration" that pattern formation in amphibian limb regeneration is a stepwise process. Since, biologist have continued to piece together the molecular components of this process to better understand the "patterning code" responsible for regenerate formation. Within this context, several different models have been proposed; however, all are based on one of two underlying hypotheses. The first is the "morphogen hypothesis" that dictates that pattern emerges from localized expression of signaling molecules, which produce differing position-specific cellular responses in receptive cells depending on the intensity of the signal. The second hypothesis is that cells in the remaining tissues retain memory of their patterning information, and use this information to generate new cells with the missing positional identities. A growing body of evidence supports the possibility that these two mechanisms are not mutually exclusive. Here, we propose our theory of hierarchical pattern formation, which consists of 4 basic steps. The first is the existence of cells with positional memory. The second is the communication of positional information through cell-cell interactions in a regeneration-permissive environment. The third step is the induction of molecular signaling centers. And the last step is the interpretation of these signals by specialized cell types to ultimately restore the limb in its entirety. Biological codes are intertwined throughout this model, and we will discuss their multiple roles and mechanisms.