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Rete ridges form via evolutionarily distinct mechanisms in mammalian skin - Nature
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The evolutionary loss of body hair in humans is a well-documented fact, yet the precise biological mechanisms driving this transition remain poorly understood. This significant reduction in hair density coincides with the emergence of a sophisticated network of epidermal structures known as rete ridges. While these ridges define human skin, the timing of their development and the molecular instructions guiding them have long been elusive. This research investigates skin development across a diverse range of mammalian species, including humans, pigs, bears, and dolphins. We discovered that rete ridges form through a cellular program fundamentally distinct from the mechanisms that generate hair follicles and sweat glands. Rather than developing as isolated units, they emerge as an interconnected network of epidermal invaginations. Our findings demonstrate that the widespread activation of the bone morphogenetic protein (BMP) signaling pathway within the epidermis is essential for creating these ridge networks, which organize themselves around underlying dermal pockets. A deeper understanding of these mechanisms may pave the way for novel therapies designed to regenerate vital skin structures lost to severe injury or chronic disease.
Human skin is a remarkably complex organ featuring specialized structures called epidermal appendages. These include hair follicles, sweat glands, fingerprint ridges, and rete ridges, which collectively support the skin's diverse physiological functions. Studying skin development across various species allows scientists to identify, classify, and understand these distinct structures. Historically, mice have served as the primary model for skin research due to their ease of handling and the extensive tools available for genetic manipulation. However, a critical limitation exists: mouse trunk skin does not form rete ridges. This absence makes it exceptionally difficult to study the developmental processes of these structures using standard laboratory mice. Consequently, the specific cellular and molecular processes responsible for rete ridge formation remained unknown until this study.
During human fetal development, rete ridges are conspicuously absent from the trunk skin. The timeline of early skin development shows that hair follicles begin to form around gestational week 12, followed by the development of sweat glands by week 19. While the dermis matures throughout mid-gestation, rete ridges remain non-existent. In stark contrast, adult and aged human skin prominently features these ridges, which coincide with a noticeable and substantial thickening of the epidermis. These ridges create an undulating, wave-like pattern along the base of the skin. The spaces beneath the areas between the ridges are occupied by highly vascularized structures known as "dermal pockets," which are rich in blood vessels.
Due to ethical limitations on studying late-stage human fetal and neonatal tissues, the precise timing of rete ridge formation has been difficult to determine. To address this gap, we turned to pigs, whose skin physiology closely resembles that of humans while being more accessible for experimental study. Our comparative analysis reveals that pig skin development mirrors the human timeline almost perfectly. Small rete ridges first become visible in pigs during late gestation. However, their primary formation occurs during the first week after birth. During this critical postnatal period, the epidermis thickens significantly, and the dermal pockets become increasingly vascularized. Rete ridge density reaches a stable plateau by the second postnatal week. These mature ridges are the primary contributors to the increased epidermal thickness observed in adulthood, a pattern that is also clearly evident in humans. We conclude that the formation of rete ridges begins around the time of birth in both species.
To understand the evolutionary context of rete ridges, we examined skin samples from a wide range of mammalian species, encompassing both terrestrial and aquatic animals.
Aquatic cetaceans, such as bottlenose dolphins, possess hairless trunk skin characterized by prominent rete ridges and an exceptionally thick epidermis. We also examined several pig breeds, all of which possess rete ridges accompanied by adjacent vascularized dermal pockets, strikingly similar to adult humans. The North American grizzly bear has large hair follicles organized into dense bundles. Interestingly, the expansive areas of skin between these follicles also contain rete ridges. In contrast, non-human primates like rhesus macaques and common marmosets have hair follicles but completely lack rete ridges. Similarly, rodents, such as mice and naked mole rats, do not form rete ridges or dermal pockets in their dorsal skin.
Our cross-species comparison revealed that species possessing rete ridges generally exhibit a significantly thicker epidermis than those without them. The ratio of rete ridge thickness to inter-ridge thickness was remarkably consistent across all ridge-bearing species, with ridges being approximately twice as thick as the surrounding tissue. This suggests a direct developmental link between the size of the dermal pocket and overall epidermal thickness. We also observed an inverse relationship between hair density and epidermal thickness: species with higher hair density tended to have thinner skin. Crucially, we found no instances of a species having a thick epidermis without rete ridges, indicating that these structures are essential for achieving and maintaining a robust skin barrier.
To test the direct relationship between hair density and epidermal thickness, we targeted an evolutionarily conserved step in hair follicle formation. This biological process involves complex signaling pathways centered on specific proteins: LEF1, WNT, EDA, and EDAR. The transcription factor LEF1 is highly expressed in the fetal epidermis of humans, primates, and rodents when hair follicles and other appendages first begin to form. However, this expression ceases entirely once placode formation concludes.
We genetically engineered mice to lack the Lef1 gene specifically within their epidermis (Lef1-eKO mice). This modification disrupted the formation of epidermal placodes, leading to a dramatic reduction in hair follicle density. The few follicles that did form failed to maintain hair growth properly. Despite this significant reduction in fur density, the thickness of the interfollicular epidermis in these mice remained completely unchanged. This crucial finding demonstrates that simply reducing hair density through genetic manipulation is not sufficient to trigger the formation of rete ridges or a thicker epidermis. Therefore, the mechanisms governing rete ridge development are fundamentally distinct from those controlling hair follicle patterning.
Our investigation into the molecular drivers of rete ridge formation began with a detailed analysis of developing pig skin. Using advanced single-cell and spatial transcriptomics, we mapped gene expression across different cell types and specific locations. This sophisticated approach allowed us to compare the molecular signatures of forming rete ridges with those of developing hair follicles and sweat glands.
The data revealed that while hair follicles and sweat glands share common initiating signals, such as EDA and WNT, rete ridge formation follows a completely different path. A key finding was the identification of a specific molecular signature in the basal epidermal cells destined to become rete ridges. This signature was characterized by the activation of the BMP signaling pathway. BMP signaling was broadly activated across the basal epidermis during the perinatal period when ridges form, in contrast to the highly localized activation seen in discrete appendages like hair follicles.
We validated the functional importance of BMP signaling using genetic models. In mice, which normally lack rete ridges in their trunk skin, we found that the specialized skin on their footpads (volar skin) does form these structures. When we genetically blocked BMP signaling specifically in the epidermis of this region, the formation of rete ridges was severely impaired. Similarly, experiments in pigs confirmed that epidermal BMP activity is necessary for proper rete ridge development. This evidence strongly supports a model where broad epidermal BMP activation drives the formation of the interconnected rete ridge network, organized around the underlying dermal pockets.
A critical question remains: can these complex structures regenerate following injury? To test this, we created full-thickness wounds on the backs of newborn pigs. Remarkably, these wounds healed and spontaneously regenerated rete ridges that were histologically similar to those in unwounded skin. Genetic lineage tracing confirmed that the regenerated ridges originated from epidermal stem cells located adjacent to the wound. This demonstrates that neonatal pig skin retains a potent innate capacity to regenerate this important epidermal architecture.
Analysis of the regenerating tissue showed that the molecular program activated during this process closely mirrored normal perinatal rete ridge development. Specifically, we observed the same broad activation of BMP signaling in the basal epidermis. This finding suggests that the mechanisms guiding development are recapitulated during regeneration, offering hope that this potential could be therapeutically harnessed in humans.
Based on our findings, we propose an evolutionary model for skin patterning in mammals. We suggest that the evolution of rete ridges involved the co-option and modification of existing molecular programs. In furry mammals, signaling pathways like WNT and EDA are used to create discrete, microscopic appendages such as hair follicles. In contrast, in species with less fur and thicker skin—like humans, pigs, bears, and dolphins—a distinct program evolved. This program utilizes broad activation of BMP signaling across the epidermis to create a continuous, interconnected network of ridges (rete ridges) rather than isolated structures.
This interconnected network provides a stable scaffold that allows for a much thicker epidermis, which is advantageous for barrier function, mechanical protection, and cellular anchoring. The dermal pockets within this network create a specialized microenvironment that supports blood vessel growth and immune cell function. This model explains why simply losing hair follicles is not enough to create thick skin; it requires the activation of this alternative, BMP-driven developmental program to build the rete ridge infrastructure.
Our study resolves a long-standing mystery in skin biology by identifying the distinct developmental timing and molecular mechanism behind rete ridge formation. We show that these structures, which are essential for a thick, robust epidermis, form perinatally through a program dependent on broad epidermal BMP signaling. This mechanism is evolutionarily distinct from those used to form hair follicles and sweat glands.
Furthermore, we demonstrate that rete ridges can regenerate in neonatal wounds, a process that reactivates the same BMP-driven developmental program. This discovery has significant therapeutic implications. Chronic wounds, severe burns, and certain skin diseases often result in the permanent loss of rete ridges, leading to fragile, scarred skin that lacks normal function. By understanding and potentially manipulating the BMP signaling pathway, it may be possible to develop new treatments that coax adult human skin to regenerate these critical structures, restoring healthy skin architecture and function after injury or disease.