BMP suppresses WNT to integrate patterning of orthogonal body axes in adult planarians

Abstract

AbstractAdult regeneration restores patterning of orthogonal body axes after damage in a post-embryonic context. Planarians regenerate using distinct body-wide signals primarily regulating each axis dimension: anteroposterior Wnts, dorsoventral BMP, and mediolateral Wnt5 and Slit determinants. How regeneration can consistently form perpendicular tissue axes without symmetry-breaking embryonic events is unknown, and could either occur using fully independent, or alternatively, integrated signals defining each dimension. Here, we report that the planarian dorsoventral regulatorbmp4suppresses the posterior determinantwnt1to pattern the anteroposterior axis. Double-FISH identified distinct anteroposterior domains within dorsal midline muscle that express eitherbmp4orwnt1. Homeostatic inhibitionbmp4andsmad1expanded thewnt1expression anteriorly, while elevation of BMP signaling throughnog1;nog2RNAi reduced thewnt1expression domain. BMP signal perturbation broadly affected anteroposterior identity as measured by expression of posterior Wnt pathway factors, without affecting head regionalization. Therefore, dorsal BMP signals broadly limit posterior identity. Furthermore,bmp4RNAi caused medial expansion of the lateral determinantwnt5and reduced expression of the medial regulatorslit. Double RNAi ofbmp4andwnt5resulted in lateral ectopic eye phenotypes, suggestingbmp4acts upstream ofwnt5to pattern the mediolateral axis. Therefore,bmp4acts at the top of a patterning hierarchy both to control dorsoventral information and also, through suppression of Wnt signals, to regulate anteroposterior and mediolateral identity. These results reveal that adult pattern formation involves integration of signals controlling individual orthogonal axes.Author SummarySystems that coordinate long-range communication across axes are likely critical for enabling tissue restoration in regenerative animals. While individual axis pathways have been identified, there is not yet an understanding of how signal integration allows repatterning across 3-dimensions. Here, we report an unanticipated linkage between anteroposterior, dorsoventral, and mediolateral systems in planarians through BMP signaling. We find that dorsally expressed BMP restricts posterior and lateral identity by suppressing distinct Wnt signals in adult planarians. These results demonstrate that orthogonal axis information is not fully independent and suggest a potentially ancient role of integrated axis patterning in generating stable 3-dimensional adult forms.