The skin is the largest organ in the body and plays critical roles in sensation, thermoregulation and protection from the environment. The outermost layer of the skin, the epidermis, is essential for animal survival, acting as a barrier to keep out toxins and microbes while preventing excessive fluid loss. The appropriate balance between cell division and differentiation is crucial for epidermis formation and maintenance. Significant advances have been made in deciphering the mechanisms of epidermis formation, homeostasis and wound response, however our understanding of the factors that control the proliferation and differentiation of epidermal keratinocytes is incomplete. This proposal focuses on the analysis of a novel mouse mutant, shorthand (shd) that displays abnormal epidermal differentiation, with the long-term objective of understanding how the affected gene regulates epidermal integrity during embryonic development and disease. There are several key steps in epidermis formation including a) the transition from a monolayer to a stratified epithelium, b) the switch from proliferation to differentiation, and c) the formation of the epidermal barrier. We will use the shd mutant, to investigate the role of the shd gene in each of these steps during epidermal development.
The Specific Aims of this proposal are to 1) define the role of shd in epidermal development, 2) determine the function of the shd gene and 3) better define the relationship between shd and known keratinocyte differentiation genes. Experiments in Aim 1 will examine the role of shd at distinct stages of epidermal development. These experiments will test how shd regulates stratification of the epidermis, keratinocyte proliferation and differentiation. Experiments in Aim 2 will focus on determining when and where the shd gene acts during epidermal development. Determining requirement for this key keratinocyte differentiation gene will broaden our understanding of the mechanisms of epidermal regulation. Experiments in Aim 3 will examine genetics and molecular interactions between shd and known epidermal regulators. These experiments will help define the architecture of the epidermal keratinocyte differentiation pathway. Defects in the regulation of epidermal proliferation and differentiation can lead to developmental defects and cancer. For example, Ikk1 and stratifin, appear to have similar developmental roles as shd and have been implicated in tumorigenesis. Thus, identifying the shd gene and defining its role in epidermis formation and differentiation should provide fundamental insights into animal and human development and provide necessary background for understanding and treating human disease.

Public Health Relevance

The skin provides a critical barrier between animals and their environment. More than a third of Americans suffer from skin disorders, including skin cancer, which accounts for half of all new cancer diagnoses, as well as ichthyoses, acute eczema and psoriases. This proposal is focused on deciphering how a critical gene acts to regulate skin formation. The mechanisms that regulate epidermal development and barrier formation are conserved across mammals, including humans thus, our studies should provide fundamental insights into animal and human development as well as disease.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Baker, Carl
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Schools of Medicine
New Haven
United States
Zip Code
Cela, P; Hampl, M; Shylo, N A et al. (2018) Ciliopathy Protein Tmem107 Plays Multiple Roles in Craniofacial Development. J Dent Res 97:108-117
Xin, Daisy; Christopher, Kasey J; Zeng, Lewie et al. (2017) IFT56 regulates vertebrate developmental patterning by maintaining IFTB complex integrity and ciliary microtubule architecture. Development 144:1544-1553
Ahn, Youngwook; Sims, Carrie; Murray, Megan J et al. (2017) Multiple modes of Lrp4 function in modulation of Wnt/?-catenin signaling during tooth development. Development 144:2824-2836
Shylo, Natalia A; Christopher, Kasey J; Iglesias, Alejandro et al. (2016) TMEM107 Is a Critical Regulator of Ciliary Protein Composition and Is Mutated in Orofaciodigital Syndrome. Hum Mutat 37:155-9
Tezuka, Tohru; Inoue, Akane; Hoshi, Taisuke et al. (2014) The MuSK activator agrin has a separate role essential for postnatal maintenance of neuromuscular synapses. Proc Natl Acad Sci U S A 111:16556-61
Mis, Emily K; Liem Jr, Karel F; Kong, Yong et al. (2014) Forward genetics defines Xylt1 as a key, conserved regulator of early chondrocyte maturation and skeletal length. Dev Biol 385:67-82
Lee, Sunjin; Kong, Yong; Weatherbee, Scott D (2013) Forward genetics identifies Kdf1/1810019J16Rik as an essential regulator of the proliferation-differentiation decision in epidermal progenitor cells. Dev Biol 383:201-13
Ahn, Youngwook; Sims, Carrie; Logue, Jennifer M et al. (2013) Lrp4 and Wise interplay controls the formation and patterning of mammary and other skin appendage placodes by modulating Wnt signaling. Development 140:583-93