All ETDs from UAB

Advisory Committee Chair

Bradley K Yoder

Advisory Committee Members

Casey Morrow

Edward J Michaud

Laura Timares

Rosa Serra

Trenton R Schoeb

Document Type

Dissertation

Date of Award

2009

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Primary cilia have been established as a nearly ubiquitous microtubule based signaling organelle, yet their function in many organs, including the hair and skin, is unknown. We hypothesized that the primary cilium would play vital roles in the hair follicle and skin based on the cilium's well characterized interactions with the Shh and Wnt developmental signaling pathways. This dissertation describes our efforts to determine the localization of the primary cilia in the murine hair follicle and assess the function of this organelle in the hair and skin. We used confocal immunofluorescence microscopy to virtually section the entire hair follicle and determined that primary cilia are on most cells of the hair follicle during development and during cycling. We were interested to determine whether the primary cilia had different functions in different cell populations such as the dermal condensate and epidermal placode of the hair follicle. We utilized the Cre-lox system to disrupt primary cilia in the dermal and epidermal portions of the hair and skin, using a dermal Cre construct Prx1-Cre and an epidermal construction K14-Cre crossed to the floxed Ift88 and Kif3a genes which when disrupted, disrupt the cilia. Using this Cre-lox construct we were able to determine that dermal primary cilia signaling is essential for proper hair follicle formation. In mice with disrupted dermal cilia, the hair follicle arrests at the hair germ stage, which coincides with loss of Shh observed phenotypes. We determined that these dermal cells lost the ability to respond to Shh signals and the hair follicle arrested. The condensate thus requires primary cilia to receive Shh signal and allow the morphogenesis of the hair follicle. Disrupted cilia in the epidermis resulted in a phenotype of mild alopecia, ectopic hair bud formation, and basal hyperplasia. We determined that primary cilia cause an expansion of the progenitor cell population by changing the axis of division of progenitor cells. They also activate the B-catenin pathway leading to ectopic hair buds. Thus, this dissertation was successful in identifying cilia in the hair and skin and establishing the primary cilia as important for hair follicle morphogenesis and epidermal homeostasis.

jid2008279x1.mov (7828 kB)
Supplemental Movie 1

jid2008279x2.mov (6574 kB)
Supplemental Movie 2

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