Universität zu Köln

Günschmann, Christian (2014). Role of Insulin/IGF-1-regulated FoxO transcription factors in epidermal morphogenesis. PhD thesis, Universität zu Köln.

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Abstract

The mammalian epidermis is a self-renewing protective epithelial barrier against external challenges and dehydration, which is formed during embryogenesis through a stratification program. The external signals that initiate and regulate this program are presently unknown. Previous findings in the laboratory identified epidermal insulin/IGF-1 signaling (IIS) as key regulators of epidermal morphogenesis. Mice with an epidermal deletion of either the insulin receptor, the IGF-1 receptor or both showed a increasing reduction in the formation of suprabasal layers, impaired proliferative potential with a temporary arrest in mitosis. The goal of this thesis was to identify how epidermal IIS controls self-renewal and stratification during embryogenesis and address the role of the IIS controlled Forkhead box-O (FoxO) transcription factors, in these processes. The results show that IIS signaling is activated in mitosis and sufficient to drive mitotic progression. Initiation of stratification is accompanied by a shift from symmetric (SCD) to asymmetric division (ACD). This shift is impaired upon loss of IIS as a result of a biased loss of ACDs. We further identified the transcription factor p63 as a downstream signaling target of IIS. P63 is a master regulator of epidermal specification, controls the shift towards ACDs and promotes proliferative potential. Upon loss of IIS, FoxO transcription factors were retained in the nucleus where they bind and inhibited p63-regulated transcription, which was independent of direct FoxO DNA binding. Small interfering- RNA mediated knockdown of FoxOs reversed IIS loss induced alterations in p63 target gene expression. Accordingly, transgenic expression of a constitutive nuclear FoxO variant in mice epidermis abrogates ACD, inhibits p63-regulated transcription and stratification, mimicking loss of p63. In summary, this study revealed a critical role for IIS-dependent control of p63 activity in coordination of ACD and stratification during epithelial morphogenesis.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Günschmann, Christian cguensch@uni-koeln.de UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-60140
Date:	18 February 2014
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	Natural sciences and mathematics Life sciences Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language epidermis English Insulin/IGF-1 English Foxo transcription factor English
Date of oral exam:	9 April 2014
Referee:	Name Academic Title Brüning, Jens Prof. Dr. Niessen, Carien Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/6014