The skin consists of the outer layer, epidermis and the underlying layer of the dermis. The dermis induces and supports the hair follicles, glands, nerves, and blood vessels in the skin. People with Focal Dermal Hypoplasia, Aplasia Cutis Congenita, large wounds, and severe burns lack normal dermis and skin function. Despite the importance of the dermis, very little is known about the embryonic origins and fate selection of dermis in different parts of the mammalian embryo. The dermis can originate from the somites, lateral plate mesoderm, and the cranial neural crest. In this proposal, we will focus on the mechanisms of emergence and Wnt signaling function in craniofacial dermal lineage. With the recent advent of elegant genetic tools, it is only now possible to combine spatial and temporal mutational analysis of signaling pathways with cell lineage studies to determine how the dermal cell identity is induced and track the movements of dermal progenitors in the context of the embryo. We have identified a critical role for beta-catenin, the central transducer of Wnt signaling, in the development of craniofacial dermis in the mouse embryo. We are uniquely poised to address the specific aims of this proposal.
In Aim1, we will characterize the emergence of the craniofacial dermal lineage with a combination of recently developed genetic lineage marking tools.
In Aim2, we will define the mechanism of Wnt signaling function in craniofacial dermal lineage by analyzing tissue-specific conditional loss and gain of beta-catenin function mutants.
In Aim3, we test the hypothesis that Dermol, the earliest dermal progenitor marker, is the critical mediator of Wnt signaling in promoting the dermal genetic program. The results from this study will provide the first comprehensive view of how the craniofacial dermis develops in the mouse embryo. Identifying the signal that promotes dermal cell fate in various progenitor tissues will enable us to guide mesenchymal stem cell differentiation along the dermal pathway and manufacture dermis that is capable of inducing hair and glands of the skin, accelerating wound healing, and restoring functional skin. The study of underlying mechanisms of dermal induction and development in different parts of the body offers an excellent model for understanding congenital dermal defects, acquired skin damage, and normal skin patterning.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE018470-03
Application #
7660409
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Scholnick, Steven
Project Start
2007-08-01
Project End
2012-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
3
Fiscal Year
2009
Total Cost
$305,601
Indirect Cost
Name
Case Western Reserve University
Department
Genetics
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Ferguson, James W; Devarajan, Mahima; Atit, Radhika P (2018) Stage-specific roles of Ezh2 and Retinoic acid signaling ensure calvarial bone lineage commitment. Dev Biol 443:173-187
Thulabandu, Venkata; Chen, Demeng; Atit, Radhika P (2018) Dermal fibroblast in cutaneous development and healing. Wiley Interdiscip Rev Dev Biol 7:
Ferguson, James; Devarajan, Mahima; DiNuoscio, Gregg et al. (2018) PRC2 Is Dispensable in Vivo for ?-Catenin-Mediated Repression of Chondrogenesis in the Mouse Embryonic Cranial Mesenchyme. G3 (Bethesda) 8:491-503
Mullin, Nathaniel K; Mallipeddi, Nikhil V; Hamburg-Shields, Emily et al. (2017) Wnt/?-catenin Signaling Pathway Regulates Specific lncRNAs That Impact Dermal Fibroblasts and Skin Fibrosis. Front Genet 8:183
Xiao, Ying; Thoresen, Daniel T; Miao, Lingling et al. (2016) A Cascade of Wnt, Eda, and Shh Signaling Is Essential for Touch Dome Merkel Cell Development. PLoS Genet 12:e1006150
Goodnough, L Henry; Dinuoscio, Gregg J; Atit, Radhika P (2016) Twist1 contributes to cranial bone initiation and dermal condensation by maintaining Wnt signaling responsiveness. Dev Dyn 245:144-56
Budnick, Isadore; Hamburg-Shields, Emily; Chen, Demeng et al. (2016) Defining the identity of mouse embryonic dermal fibroblasts. Genesis 54:415-30
Hamburg-Shields, Emily; DiNuoscio, Gregg J; Mullin, Nathaniel K et al. (2015) Sustained ?-catenin activity in dermal fibroblasts promotes fibrosis by up-regulating expression of extracellular matrix protein-coding genes. J Pathol 235:686-97
Vithayathil, Joseph; Pucilowska, Joanna; Goodnough, L Henry et al. (2015) Dentate Gyrus Development Requires ERK Activity to Maintain Progenitor Population and MAPK Pathway Feedback Regulation. J Neurosci 35:6836-48
Goodnough, L Henry; Dinuoscio, Gregg J; Ferguson, James W et al. (2014) Distinct requirements for cranial ectoderm and mesenchyme-derived wnts in specification and differentiation of osteoblast and dermal progenitors. PLoS Genet 10:e1004152

Showing the most recent 10 out of 17 publications