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First published online 2 December 2004
doi: 10.1242/dev.01563

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Mouse Disp1 is required in sonic hedgehog-expressing cells for paracrine activity of the cholesterol-modified ligand

Hua Tian^1,*, Juhee Jeong^2,*, Brian D. Harfe³, Clifford J. Tabin⁴ and Andrew P. McMahon^5,

¹ One DNA Way, Genentech Incorporated, South San Francisco, CA 94080, USA
² 1550 Fourth Street, Room 282, UCSF Mission Bay Campus, San Francisco, CA 94158, USA
³ University of Florida College of Medicine, Department of Molecular Genetics and Microbiology, 1600 SW Archer Road, Gainesville, FL 32610-0266, USA
⁴ Department of Genetics, Harvard Medical School, NRB room 360, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
⁵ Department of Molecular and Cellular Biology, The Biolabs, Harvard University, 16 Divinity Avenue, Cambridge, MA 02138, USA

Author for correspondence (e-mail: mcmahon{at}mcb.harvard.edu)

Accepted 4 November 2004

Previous studies have demonstrated that Disp1 function is essential for Shh and Ihh signaling in the mouse, and Disp1 gene dose regulates the level of Shh signaling activity in vivo. To determine whether Disp1 activity is required in Shh-producing cells for paracrine signaling in Shh target fields, we used a Shh^GFP-Cre (here shortened to Shh^Cre) knock-in allele and a Disp1 conditional allele to knock down Disp1 activity specifically within Shh-producing cells. The resulting facial and neural tube phenotypes support the conclusion that the primary and probably exclusive role for Disp1 is within hedgehog protein-producing cells. Furthermore, using an allele that produces N-Shh (a noncholesterol modified form of the Shh protein), we demonstrate that N-Shh is sufficient to rescue most of the early embryonic lethal defects in a Disp1-null mutant background. Thus, Disp1 activity is only required for paracrine hedgehog protein signaling by the cholesterol modified form of Shh (N-Shhp), the normal product generated by auto-processing of a Shh precursor protein. In both respects, Disp function is conserved from Drosophila to mice.

Key words: Dispatched1, Shh, Cholesterol, Paracrine, Autocrine

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