Letters to Nature

Nature 423, 448-452 (22 May 2003) | doi:10.1038/nature01611; Received 12 February 2003; Accepted 20 March 2003; Published online 27 April 2003

Wnt proteins are lipid-modified and can act as stem cell growth factors

Karl Willert1, Jeffrey D. Brown1, Esther Danenberg1, Andrew W. Duncan2, Irving L. Weissman3, Tannishtha Reya2, John R. Yates, III4 & Roel Nusse1

  1. Howard Hughes Medical Institute and Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA
  2. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA
  3. Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA
  4. Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, USA

Correspondence to: Roel Nusse1 Correspondence and requests for materials should be addressed to R.N. (Email: rnusse@cmgm.stanford.edu).

Wnt signalling is involved in numerous events in animal development1, including the proliferation of stem cells2 and the specification of the neural crest3. Wnt proteins are potentially important reagents in expanding specific cell types, but in contrast to other developmental signalling molecules such as hedgehog proteins and the bone morphogenetic proteins, Wnt proteins have never been isolated in an active form. Although Wnt proteins are secreted from cells4, 5, 6, 7, secretion is usually inefficient8 and previous attempts to characterize Wnt proteins have been hampered by their high degree of insolubility. Here we have isolated active Wnt molecules, including the product of the mouse Wnt3a gene. By mass spectrometry, we found the proteins to be palmitoylated on a conserved cysteine. Enzymatic removal of the palmitate or site-directed and natural mutations of the modified cysteine result in loss of activity, and indicate that the lipid is important for signalling. The purified Wnt3a protein induces self-renewal of haematopoietic stem cells, signifying its potential use in tissue engineering.