Tumor Necrosis Factors and Chemokines in Hair Development

Several embryonic organs, such as the hair follicle, develop as appendages of the ectoderm, the outermost layer of the embryo. These organs develop as a result of reciprocal tissue interactions between the surface epithelium and the underlying mesenchyme. The fi rst morphological sign of a developing hair follicle is a thickening of the epithelium called a placode. Several major signaling pathways are important for the development of hair and other ectodermal organs such as Wnts, fi broblast growth factors (Fgfs), Transforming growth factor-beta (TGF-beta), Hedgehogs (Hh) and tumor necrosis factors (TNFs). This thesis focuses on the role of TNFs in hair development and more particularly on one member of the TNF superfamily: Ectodysplasin (Eda). Mutations in Eda pathway components including the TNF ligand Eda, its receptor (Edar), and downstream effectors essential for activation of transcription factor NFbappaB in mouse or human give rise to a disease called hypohidrotic ectodermal dysplasia (HED). HED is an inherited disorder characterized by impaired development of ectodermal organs such as hair, teeth and several exocrine glands. A hallmark of mouse HED (Eda null mouse) is the absence of primary hair placodes that form at embryonic day 14 (E14). In order to identify the direct target genes of Eda, we have performed a microarray analysis on genes differentially expressed upon short exposure to recombinant Eda protein on Eda null skin at E14. Several of the genes identifi ed belong to the major signaling pathways mentioned above and interestingly, include also six chemokines that have not previously been associated with hair follicle morphogenesis. The purpose of this study was to validate whether the upregulated genes were truly transcriptional target genes of Eda/NFkappaB and to study their functional relevance in ectodermal organogenesis, in particular in hair follicle development. Based on these studies, we were able to confirm some Wnt pathway members, such as Dkk4 and Lrp4,TNF family member A20, and two chemokines, cxcl10 and cxcl11, as likely direct target genes of Eda. It is shown that whereas Dkk4 and Lrp4 are expressed in all ectodermal organs, A20 and the two chemokines seem to be hair follicle specific. Further study of Dkk4 and Lrp4 during development led us to conclude that Wnt and Eda pathways interact closely to fine tune the development of hair and other ectodermal organs. The role of A20 seems to be restricted to the termination of NFkappaB signaling induced by the Eda pathway in hair follicles. The lack of cxcl10 and cxcl11 signaling during hair follicle formation leads to more widely spaced hair placodes. This work has revealed an important role of Eda during hair placode induction as a modulator of inhibitors and activators of the major pathways in order to direct the patterning of hair placodes.

Grantor dc:publisher

Helsingin yliopisto

Year dc:date.issued

2012

Author dc:creator

• Lefebvre, Sylvie

• kehitysbiologia

Statement dc:rights

• Julkaisu on tekijänoikeussäännösten alainen. Teosta voi lukea ja tulostaa henkilökohtaista käyttöä varten. Käyttö kaupallisiin tarkoituksiin on kielletty.
• This publication is copyrighted. You may download, display and print it for Your own personal use. Commercial use is prohibited.
• Publikationen är skyddad av upphovsrätten. Den får läsas och skrivas ut för personligt bruk. Användning i kommersiellt syfte är förbjuden.

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/10138/33618

OAI record oai:identifier

https://helda.helsinki.fi/server/oai/request?verb=GetRecord&metadataPrefix=dim&identifier=oai%3Ahelda.helsinki.fi%3A10138%2F33618