Planarian dorsoventral Netrins control a muscle midline signaling center and regulate blastema formation

Abstract

AbstractIntegration of positional information across body axes is likely critical for whole-body regeneration to define the territories of missing tissue in three dimensions with fidelity. The body-wall musculature in planarians expresses patterning factors regulating the anteroposterior, dorsoventral, and mediolateral axes, but how this information coordinates is not fully understood. We identify a previously described factor specifically expressed in dorsal midline muscle as a BMP/Activin decoy receptorbambi-2. Analysis of scRNAseq indicatesbambi-2+cells coexpress midline-specifying transcription factorpitxand longitudinal muscle-specifying factormyoD, and production ofbambi-2+cells requires these factors. In laterally amputated animals regenerating an entirely new midline,bambi-2+cells are initially formed at the wound site, then dynamically spread, and ultimately reset to restore bilateral symmetry. We further identify a system of dorsoventral Netrin and Netrin receptor signals expressed from body-wall muscle that control midline identity and blastema morphology. Ventral and laterally expressednetrins -1, -4,and-5signal via dorsally-enriched netrin repulsion receptorsunc5-C, unc5-E,anddcc-2, which together limit mediolateral spread ofbambi-2+dorsal midline muscle and influence the architecture of the muscle system. Our results suggest a model in which ventral determinants dictate mediolateral information important for blastema morphology.