Biology subjects

Kamberov, Y. G.

Publications and source records attributed to Kamberov, Y. G..

5 recordsLinked to original sources

bioRxiv2023

A transient dermal niche and dual epidermal programs underlie sweat gland development

Eccrine glands are mammalian skin appendages indispensable for human thermoregulation. Like all skin-derived appendages, eccrine glands form from multipotent progenitors in the basal skin epidermis. It remains unclear how epidermal progenitors progressively specialize to specifically form eccrine glands, precluding efforts to regenerate these vital organs. Herein, we applied single nucleus transcriptomics to compare the expression content of wildtype, eccrine-forming mouse skin to that of mice harboring a skin-specific disruption of Engrailed 1 (En1), a transcription factor that promotes the formation of eccrine glands in both humans and mice. We identify two concurrent epidermal transcriptomes in the earliest eccrine anlagen: a predominant transcriptome that is shared with hair follicles, and a vastly underrepresented transcriptome that is En1-dependent and eccrine-specific. We demonstrate that differentiation of the eccrine anlage requires the induction of a transient and transcriptionally unique dermal niche that forms around each developing gland in humans and mice. Our study defines the transcriptional determinants underlying eccrine identity in the epidermis and uncovers the dermal niche required for eccrine developmental progression. By identifying these defining components of the eccrine developmental program, our findings set the stage for directed efforts to regenerate eccrine glands for comprehensive skin repair.

developmental biology↗

bioRxiv2022

Differential modularity of the mammalian Engrailed 1 enhancer network directs eccrine sweat gland development

Enhancers are context-specific regulators of expression that drive biological complexity and variation through the redeployment of conserved genes. An example of this is the enhancer-mediated control of the transcription of Engrailed 1 (EN1), a pleiotropic gene whose expression is required for the specification of eccrine sweat glands in mammals. We have previously identified an enhancer, ECE18 that has been highly and repeatedly derived on the human lineage to potentiate ectodermal EN1 and induce our species uniquely high eccrine gland density. Intriguingly, ECE18 quantitative activity is negligible outside of primates and ECE18 is not required for En1 regulation and eccrine gland specification in mice, raising the possibility that distinct enhancers have evolved to modulate the same trait. Here we report the identification of the ECE20 enhancer and show it has conserved functionality in mouse and human developing skin ectoderm. Unlike ECE18, knock-out of ECE20 in mice reduces ectodermal En1 and eccrine gland number. Notably, we find ECE20, but not ECE18, is also required for En1 expression in the embryonic mouse brain, demonstrating that ECE20 is a pleiotropic En1 enhancer. Finally, that ECE18 deletion does not potentiate the eccrine phenotype of ECE20 knockout mice supports the secondary incorporation of ECE18 into the regulation of this trait in primates. Our findings reveal that the mammalian En1 regulatory machinery diversified to incorporate both shared and lineage-restricted enhancers to regulate the same phenotype, and also have implications for understanding the forces that shape the robustness and evolvability of developmental traits.

evolutionary biology↗

bioRxiv2022

Ectodysplasin signaling via Xedar is required for mammary gland morphogenesis

The Ectodysplasin A2 receptor (XEDAR), is a member of the tumor necrosis factor receptor subfamily and is a mediator of the Ectodysplasin (EDA) signaling pathway. EDA signaling plays evolutionarily conserved roles in the development of the ectodermal appendage organ class that includes hair, eccrine sweat glands, and mammary glands. Loss of function mutations in Eda, which encodes the two major ligand isoforms, EDA-A1 and EDA-A2, result in X-linked hypohidrotic ectodermal dysplasia (XLHED), which is characterized by defects in two or more ectodermal appendage types. EDA-A1 and EDA-A2 signal through the receptors EDAR and XEDAR, respectively. While the contributions of the EDA-A1/EDAR signaling pathway to ectodermal appendage phenotypes have been extensively characterized, the significance of the EDA-A2/XEDAR branch of the pathway has remained obscure. Herein, we report the phenotypic consequences of disrupting the EDA-A2/XEDAR pathway on mammary gland differentiation and growth. Using a mouse Xedar knock-out model, we show that Xedar has a specific and temporally restricted role in promoting post-pubertal growth and branching of the mammary epithelium that can be influenced by genetic background. Our findings are the first to implicate Xedar in ectodermal appendage development and suggest that the EDA-A2/XEDAR signaling axis contributes to the etiology of EDA-dependent mammary phenotypes.

developmental biology↗

bioRxiv2020

An Engrailed1 enhancer underlies human thermoregulatory evolution

Humans rely on sweating to cool off and have the highest eccrine sweat gland density among mammals. We investigated whether altered regulation of the Engrailed 1 (EN1) gene, the levels of which are critical for patterning eccrine glands during development, could underlie the evolution of this defining human trait. First, we identify five EN1 candidate enhancers (ECEs) using comparative genomics and validation of enhancer activity in mouse skin. The human ortholog of one ECE, hECE18, contains multiple derived substitutions that together dramatically increase the activity of this enhancer in keratinocytes. Targeted repression of hECE18 reduces EN1 expression in human keratinocytes, indicating hECE18 upregulates EN1 in this context. Finally, we find that hECE18 increases ectodermal En1 in a humanized knock-in mouse to increase eccrine gland number. Our study uncovers a genetic basis for the evolution of one of the most singular human adaptations and implicates the recurrent mutation of a single enhancer as a novel mechanism for evolutionary change.

evolutionary biology↗

bioRxiv2018

Comparative evidence for the independent evolution of hair and sweat gland traits in primates

Humans differ in many respects from other primates, but perhaps no derived human feature is more striking than our naked skin. Long purported to be adaptive, humans unique external appearance is characterized by changes in both the patterning of hair follicles and eccrine sweat glands, producing decreased hair cover and increased sweat gland density. Despite the conspicuousness of these features and their potential evolutionary importance, there is a lack of clarity regarding how they evolved within the primate lineage. We thus collected and quantified the density of hair follicles and eccrine sweat glands from five regions of the skin in three species of primates: macaque, chimpanzee and human. Although human hair cover is greatly attenuated relative to that of our close relatives, we find that humans have a chimpanzee-like hair density that is significantly lower than that of macaques. In contrast, eccrine gland density is on average 10-fold higher in humans compared to chimpanzees and macaques, whose density is strikingly similar. Our findings suggest that a decrease in hair density in the ancestors of humans and apes was followed by an increase in eccrine gland density and a reduction in fur cover in humans. This work answers longstanding questions about the traits that make human skin unique and substantiates a model in which the evolution of expanded eccrine gland density was exclusive to the human lineage.

evolutionary biology↗