Shh-mediated degradation of Hhip allows cell autonomous and non-cell autonomous Shh signalling

Lina Kwong, Maarten F. Bijlsma and Henk Roelink ()
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Lina Kwong: University of California, 16 Barker Hall, 3204
Maarten F. Bijlsma: Laboratory for Experimental Oncology and Radiobiology, Center of Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam
Henk Roelink: University of California, 16 Barker Hall, 3204

Nature Communications, 2014, vol. 5, issue 1, 1-9

Abstract: Abstract The distribution of Sonic Hedgehog (Shh) is a highly regulated and critical process for development. Several negative feedback mechanisms are in place, including the Shh-induced upregulation of Hedgehog-interacting protein (Hhip). Hhip sequesters Shh, leading to a non-cell autonomous inhibition of the pathway. Hhip overexpression has a severe effect on neural tube development, raising the question why normal sites of Hhip expression have a seemingly unimpaired response to Shh. Here we show that although Hhip is able to leave its sites of synthesis to inhibit Shh non-cell autonomously, activation of Smoothened (Smo) drastically increases Hhip internalization and degradation cell autonomously. Although Hhip is unable to cell autonomously inhibit the consequences of Smo activation, it can inhibit the Shh response non-cell autonomously. Our data provide a mechanism by which the Shh ligand can activate the response and negate cell autonomous effects of Hhip, while Hhip can still induce non-cell autonomous inhibition.

Date: 2014
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DOI: 10.1038/ncomms5849

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