Rete ridges form via evolutionarily distinct mechanisms in mammalian skin

The loss of fur during human evolution has long mystified scientists and the public. Reduced hair density coincides with the acquisition of epidermal rete ridges, whose developmental timing and molecular mechanisms are poorly understood despite their prominence in humans. Examination of human and pig skin development revealed that rete ridges form through an independent mechanism from hair follicles and sweat glands by establishing interconnected epidermal invaginations. We documented rete ridge occurrence across Mammalia, including in grizzly bears and dolphins, and showed that neonatal pig wounds can regenerate them de novo. Multi-species spatiotemporal transcriptomics identified significant signaling interactions between epidermal and dermal cells during rete ridge morphogenesis, particularly through BMP. We also demonstrated that murine fingerpad skin forms rete ridges and functionally requires epidermal BMP signaling. We propose that evolution of rete ridges in mammalian skin involved replacement of the molecular program for formation of discrete microscopic appendages, including hair follicles and sweat glands, with a distinct program for the interconnected appendage network. Broad epidermal activation of BMP is required for the development of rete ridge networks organized around underlying dermal pockets. Understanding rete ridge mechanisms may enable the development of therapeutic approaches to regenerate epidermal appendages lost during wounding or disease in humans. Overall design: Skin from a E90 fetal pig, P3 neonatal pig, P10 neonatal pig, and 6-month old adult pig was collected under approved protocols and processed to generate a single-cell suspension from the epidermis and dermis in 1:1 ratios for 10x Genomics scRNA-seq. Additionally, we re-analyzed previously published scRNA-seq datasets from Glover et al., 2023; Cheng et al., 2018; Solé-Boldo et al., 2020; Liu et al., 2022 based on their published sequencing files. Finally, skin from P3, P10, and 6mo pigs were processed to generate spatial transcriptomics datasets using Complete Genomics Stereo-seq. *************************************************************** The table below lists GEO accessions reused/reanalyzed for this study. ***************************************************************