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Molecular and Cellular Biology, June 2007, p. 4454-4464, Vol. 27, No. 12
0270-7306/07/$08.00+0     doi:10.1128/MCB.00133-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Viable Mice with Compound Mutations in the Wnt/Dvl Pathway Antagonists nkd1 and nkd2

Shu Zhang,¹ Tolga Çagatay,¹ Manami Amanai,^1, Mei Zhang,^1,¶ Janine Kline,^4, Diego H. Castrillon,¹ Raheela Ashfaq,¹ Orhan K. Öz,³ and Keith A. Wharton Jr.^1,2*

Department of Pathology,¹ Department of Molecular Biology,² Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390,³ Department of Developmental Biology, Howard Hughes Medical Institute, Beckman Center, Stanford University School of Medicine, Stanford, California 94305⁴

Received 21 January 2007/ Returned for modification 27 February 2007/ Accepted 22 March 2007

Gradients of Wnt/ß-catenin signaling coordinate development and physiological homeostasis in metazoan animals. Proper embryonic development of the fruit fly Drosophila melanogaster requires the Naked cuticle (Nkd) protein to attenuate a gradient of Wnt/ß-catenin signaling across each segmental anlage. Nkd inhibits Wnt signaling by binding the intracellular protein Dishevelled (Dsh). Mice and humans have two nkd homologs, nkd1 and nkd2, whose encoded proteins can bind Dsh homologs (the Dvl proteins) and inhibit Wnt signaling. To determine whether nkd genes are necessary for murine development, we replaced nkd exons that encode Dvl-binding sequences with IRES-lacZ/neomycin cassettes. Mutants homozygous for each nkd^lacZ allele are viable with slightly reduced mean litter sizes. Surprisingly, double-knockout mice are viable, with subtle alterations in cranial bone morphology that are reminiscent of mutation in another Wnt/ß-catenin antagonist, axin2. Our data show that nkd function in the mouse is dispensable for embryonic development.

Published ahead of print on 16 April 2007.

Present address: Laboratory of Mammalian Molecular Embryology, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan.

^¶ Present address: Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC 27710.

Present address: Novartis, Emeryville, CA 94601.