Failure of digit tip regeneration in the absence of Lmx1b suggests Lmx1b functions disparate from dorsoventral polarity

Mammalian digit tip regeneration is linked to the presence of nail tissue, but a nail-explicit model is missing. Here, we report that nail-less double-ventral digits of ΔLARM1/2 mutants that lack limb-specific Lmx1b enhancers fail to regenerate. To separate the nail’s effect from the lack of dorsoventral (DV) polarity, we also interrogate double-dorsal double-nail digits and show that they regenerate. Thus, DV polarity is not a prerequisite for regeneration, and the nail requirement is supported. Transcriptomic comparison between wild-type and non-regenerative ΔLARM1/2 mutant blastemas reveals differential upregulation of vascularization and connective tissue functional signatures in wild type versus upregulation of inflammation in the mutant. These results, together with the finding of Lmx1b expression in the postnatal dorsal dermis underneath the nail and uniformly in the regenerative blastema, open the possibility of additional Lmx1b roles in digit tip regeneration, in addition to the indirect effect of mediating the formation of the nail. [Display omitted] •In the absence of Lmx1b, ventral-ventral digits form that lack regenerative capacity•Dorsoventral polarity is not required for digit tip regeneration•Lmx1b is expressed in the nail dermis and throughout the regenerative blastema•Amputations of Lmx1b-deficient digits form small blastemas but fail to progress Castilla-Ibeas et al. analyze digit tip regeneration in mutants with double-ventral or double-dorsal digits and demonstrate that dorsoventral polarity is dispensable for regeneration. They also observe expression of Lmx1b, the dorsal limb determinant, in the postnatal dorsal dermis and regenerative blastema, suggesting direct roles for Lmx1b in regeneration.