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First published online December 12, 2006
doi: 10.1242/10.1242/dev.02708
1 Institute of Biotechnology, Developmental Biology Program, University of
Helsinki, 00014 Helsinki, Finland.
2 Department of Biochemistry, University of Lausanne, 1066 Epalinges,
Switzerland.
* Authors for correspondence (e-mail: irma.thesleff{at}helsinki.fi; marja.mikkola{at}helsinki.fi)
Accepted 20 October 2006
Ectodermal organogenesis is regulated by inductive and reciprocal
signalling cascades that involve multiple signal molecules in several
conserved families. Ectodysplasin-A (Eda), a tumour necrosis factor-like
signalling molecule, and its receptor Edar are required for the development of
a number of ectodermal organs in vertebrates. In mice, lack of Eda
leads to failure in primary hair placode formation and missing or abnormally
shaped teeth, whereas mice overexpressing Eda are characterized by
enlarged hair placodes and supernumerary teeth and mammary glands. Here, we
report two signalling outcomes of the Eda pathway: suppression of bone
morphogenetic protein (Bmp) activity and upregulation of sonic hedgehog (Shh)
signalling. Recombinant Eda counteracted Bmp4 activity in developing teeth
and, importantly, inhibition of BMP activity by exogenous noggin partially
restored primary hair placode formation in Eda-deficient skin in
vitro, indicating that suppression of Bmp activity was compromised in the
absence of Eda. The downstream effects of the Eda pathway are likely to be
mediated by transcription factor nuclear factor-
B (NF-
B), but
the transcriptional targets of Edar have remained unknown. Using a
quantitative approach, we show in cultured embryonic skin that Eda induced the
expression of two Bmp inhibitors, Ccn2/Ctgf (CCN family protein 2/connective
tissue growth factor) and follistatin. Moreover, our data indicate that Shh is
a likely transcriptional target of Edar, but, unlike noggin, recombinant Shh
was unable to rescue primary hair placode formation in Eda-deficient
skin explants.
Key words: Ccn2, Ectodermal dysplasia, Lateral inhibition, NF-
B, Tabby, Mouse
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