MicroRNAs linked to mammalian skin development

Since their discovery, microRNAs have been shown to play a role in the development of many organisms, including plants and insects but, until now, no one had linked them to developmental processes in humans or other mammals. This week, new research from Rockefeller University firmly establishes microRNAs as an essential element in the proper development of mammalian skin.

Growing hair. Normally, as hair develops, follicle cells (in green) grow downward to anchor the hair in the skin’s underlying dermis. Scientists have shown that tiny strands of RNA, called microRNAs, play a key role in this process — when microRNAs are removed from mice skin and hair cells, the follicle cells instead grow upwards and form clumps along the skin’s epidermis (red).

In a paper published in Nature Genetics, Elaine Fuchs, head of Rockefeller’s Laboratory of Mammalian Cell Biology and Development, and colleagues announce that they have found and characterized over one hundred microRNAs in the outer layer and hair follicles of mouse skin. These microRNAs, tiny chunks of RNA that bind to longer segments in order to turn off the production of proteins, are key to the mice’s ability to develop hair follicles and oil glands, the scientists say.

Initially identified in the C. elegans worm in 1993, microRNAs have generated escalated interest since 2000, and their ability to give cells another level of regulation for protein production, helping fine-tune specific actions and responses, is now considered critical to many cellular processes. Specific microRNAs have been associated with several cancers, including colon and lung cancers and lymphoma, and even with the body’s response to viruses such as HIV.

Fuchs and her colleagues focus on how the epidermis and hair follicles develop from stem cells. It was a postdoctoral fellow in Fuchs’s lab, Rui Yi, who found that although many microRNAs are produced by both epidermal and hair follicle cells, there is little overlap between the two groups of expressed microRNAs. What’s more, within each of the two groups, the different microRNAs expressed can be easily assigned into families. “MicroRNAs are classified based upon the putative target mRNAs that they are predicted to recognize, bind to and suppress,” says Fuchs. “We discovered that families of microRNAs with shared predicted targets are co-expressed as groups in either the epidermis or the hair follicle. Our findings uncover a novel type of regulatory network that controls the coordinate expression of microRNA families. It also implies that there are distinct target mRNAs that are differentially repressed by the microRNAs of the epidermis and the hair follicle.” Fuchs and Rui, who is the first author of the paper, suggest that the coordinated expression of microRNA families may serve as a reinforcement mechanism to effectively and rapidly suppress RNA targets during stem cell differentiation and lineage specification.

Using a mouse line developed in the laboratory of Rockefeller’s Alexander Tarakhovsky, Yi was able to completely remove all microRNAs from the skin of the mice and examine the consequences. He found that while skin development appeared normal, within six days after they were born, the mice had lost weight and become dehydrated.

When the scientists looked closer, they saw that the development of the hair follicles was markedly perturbed. Instead of growing down into the underlying dermal skin layer as they normally would, the developing follicles grew upwards into the overlying epidermis. Hair-like cysts developed that soon disturbed the surrounding skin epidermis, compromising its ability to perform its function as a barrier to retain fluids in the body.

Other appendages in epidermal tissues, including papillae in the tongue and sweat glands in the feet of the mice, were also malformed, and may have contributed to the weight loss and dehydration of the mice as they aged.

“We have shown the microRNAs exist in the skin and that they do play an important role in its development,” says Fuchs. “We now have a basis to probe more deeply into their individual roles and deepen our understanding of skin biology.”element in the proper development of mammalian skin.

In a paper published in Nature Genetics, Elaine Fuchs, head of Rockefeller’s Laboratory of Mammalian Cell Biology and Development, and colleagues announce that they have found and characterized over one hundred microRNAs in the outer layer and hair follicles of mouse skin. These microRNAs, tiny chunks of RNA that bind to longer segments in order to turn off the production of proteins, are key to the mice’s ability to develop hair follicles and oil glands, the scientists say.

Initially identified in the C. elegans worm in 1993, microRNAs have generated escalated interest since 2000, and their ability to give cells another level of regulation for protein production, helping fine-tune specific actions and responses, is now considered critical to many cellular processes. Specific microRNAs have been associated with several cancers, including colon and lung cancers and lymphoma, and even with the body’s response to viruses such as HIV.

Fuchs and her colleagues focus on how the epidermis and hair follicles develop from stem cells. It was a postdoctoral fellow in Fuchs’s lab, Rui Yi, who found that although many microRNAs are produced by both epidermal and hair follicle cells, there is little overlap between the two groups of expressed microRNAs. What’s more, within each of the two groups, the different microRNAs expressed can be easily assigned into families. “MicroRNAs are classified based upon the putative target mRNAs that they are predicted to recognize, bind to and suppress,” says Fuchs. “We discovered that families of microRNAs with shared predicted targets are co-expressed as groups in either the epidermis or the hair follicle. Our findings uncover a novel type of regulatory network that controls the coordinate expression of microRNA families. It also implies that there are distinct target mRNAs that are differentially repressed by the microRNAs of the epidermis and the hair follicle.” Fuchs and Rui, who is the first author of the paper, suggest that the coordinated expression of microRNA families may serve as a reinforcement mechanism to effectively and rapidly suppress RNA targets during stem cell differentiation and lineage specification.

Using a mouse line developed in the laboratory of Rockefeller’s Alexander Tarakhovsky, Yi was able to completely remove all microRNAs from the skin of the mice and examine the consequences. He found that while skin development appeared normal, within six days after they were born, the mice had lost weight and become dehydrated.

When the scientists looked closer, they saw that the development of the hair follicles was markedly perturbed. Instead of growing down into the underlying dermal skin layer as they normally would, the developing follicles grew upwards into the overlying epidermis. Hair-like cysts developed that soon disturbed the surrounding skin epidermis, compromising its ability to perform its function as a barrier to retain fluids in the body.

Other appendages in epidermal tissues, including papillae in the tongue and sweat glands in the feet of the mice, were also malformed, and may have contributed to the weight loss and dehydration of the mice as they aged.

“We have shown the microRNAs exist in the skin and that they do play an important role in its development,” says Fuchs. “We now have a basis to probe more deeply into their individual roles and deepen our understanding of skin biology.”