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 DLARM1/2 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 DLARM1/2 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.

Acknowledgments: Supported by funds from the Spanish Ministry of Science and Innovation Grant PID2020-114525GB-I00 to M.R. and from the Pathology Research endowment, the S. H. Crook’s Chair to K.C.O. A.C.-I. is supported by Spanish Ministry of Science and Innovation PhD fellowship PRE2018-083421. S.Z. was supported by a PhD fellowship from the Universidad de Cantabria. SHG imaging and analysis was conducted at the Microscopy & Dynamic Imaging Unit, CNIC, ICTS-ReDib, co-funded by MCIN/AEI/10.13039/501100011033. We thank Can Aztekin for critical reading, Irene Mate for technical support, and the Animal Facility of the Universidad de Cantabria for outstanding animal husbandry