Molecular mechanisms of regeneration initiation and dorsal-ventral patterning in planarians

Abstract

Regeneration is widespread among animals, yet very little is known about the molecular mechanisms that govern regenerative processes. Planarians have emerged in recent years as a powerful model for studying regeneration and are capable of whole-body regeneration following a limitless variety of injuries. Two major questions in planarian regeneration have been: 1) how are the identities of missing tissues determined?; and 2) how is the decision to mount a regenerative response to injury mediated? As part of an effort to address question 1), the mechanism by which dorsoventral (DV) pattern is regenerated following amputation was investigated. A planarian homolog of the Bmp family gene admp was identified and found to be required for regeneration of lateral tissues as well as the proper regeneration and maintenance of DV polarity. Subsequently, a regulatory relationship between admp and a bmp homolog was described. In this regulatory circuit, admp activates bmp expression but bmp represses admp expression. This arrangement results in a DV regulatory circuit that is buffered against perturbation and able to mediate robust DV and mediolateral regeneration. Question 2) was investigated by cloning several wound-induced genes and assaying for roles in regeneration initiation. A homolog of the TGF-[beta] inhibitor follistatin was identified in this manner and found to be required for regeneration. Furthermore,follistatin was required for mounting a number of regeneration-specific responses to injury. A suppression screen of candidate planarian TGF-[beta] genes identified an activin homolog, act-1, as a probable target of Follistatin inhibition. act-i suppressed regeneration-specific responses to injury and was required for terminating some regenerative processes after regeneration was complete. From these data, a model was formulated in which Follistatin-mediated inhibition of Act-1 is required for regeneration initiation and relief of this inhibition is subsequently required for regeneration termination.