Figure 8. zic-1 function couples injury signaling and polarized Wnt signaling cues for activation of stem cells to produce the anterior pole in early head regeneration.

Anterior pole formation is neoblast-dependent, specific to anterior-facing amputations and midline cues, and dependent on foxD and zic-1. Prior to 24 hours, injury-induced expression of notum and wnt1 (not depicted) in collagen+ body wall muscle cells engages a decision process that determines anterior versus posterior identity at an amputation site. At anterior-facing amputation sites, this results in a low canonical Wnt signaling environment which promotes anterior identity and, directly or indirectly, expression of zic-1 in a population of smedwi-1+ neoblasts, some of which are foxD+. By 48 hours, zic-1 promotes specification of notum+smedwi-1+ progenitors that form an anterior pole signaling center that expresses zic-1, foxD, follistatin and notum. Signaling from the anterior pole, likely including notum activity, suppresses Wnt signaling to promote head outgrowth and patterning. Experimental inhibition of beta-catenin-1 can fulfill the signal inhibitory function of notum necessary for head formation in the absence of zic-1 or the anterior pole. zic-1 expression preferential to anterior-facing amputation sites ensures anterior-specific utilization of foxD+smedwi-1+ progenitors that are formed at both anterior and posterior injury sites.