Re: in which metabolic pathways Frizzled genes are engaged?

Dear Luca,

Thanks for your question!

The frizzled gene family encodes a group of 7-transmembrane domain proteins, related to the Drosophila frizzled (fz) gene. Currently, the proposed role for these proteins, in any model organism, is that they act as cell-surface receptors for the wingless (wg)/Wnt family of secreted proteins. However, our understanding of frizzled gene function is incomplete, and it is certainly possible that these genes fulfill other roles.

Given our limited knowledge of the roles of frizzled genes, I am only able to address their function in terms of wg/Wnt signaling. Since you indicated that you are particularly interested in information regarding mouse, I will restrict my discussion accordingly. However, much of our knowledge has come from studies of the wingless (wg) gene in Drosophila and you may want to take a look at the review articles I have listed at the end, which cover some of this information.

Wg/Wnt genes
Wnt genes are defined by DNA sequence homology to the original members of this family, wingless in Drosophila and Wnt-1 (orginally called int-1) in mouse. Generally speaking, Wnt proteins are now recognized as one of the major classes of important signaling molecules in embryonic development. They are involved in such diverse processes as embryonic induction, the generation of cell polarity, and the specification of cell fate. In addition, evidence is emerging that implicates a number of the Wnt signaling components in the origin of human cancer. In fact, the mouse Wnt-1 was first identified for its ability to form mouse mammary tumors when misexpressed.

Wnt genes in mouse development and oncogenesis
Most of what is known about Wnt gene function in the mouse comes from studies of gene knockouts (a process whereby the normal gene of interest is deleted). I should tell you that the terminology in this field is somewhat confusing--there are several Wnt genes in the mouse, as well as several frizzled genes. In the interest of brevity, I will only give a sampling of some of the roles of Wnts in the mouse. For a more comprehensive, detailed list you may want to look at "Evolutionary Homologs" link from the Drosophila wingless page on the Interactive Fly website. Mouse Wnt3A, for example, is involved in the development of paired segmental structures called somites, which contribute to portions of the axial skeleton, as well as the muscles of the body wall and developing limbs. Mouse Wnt7A, on the other hand, seems to be involved in patterning the developing limbs along the dorsal/ventral and anterior/posterior axes (for instance, making the back of your hand different from the palm and your little finger different from your thumb). Mouse Wnt4 is important in kidney development and Wnt2 is associated with mammary development. In terms of the role of Wnt genes in cancer, there is some interesting data that is accumulating. Although Wnt-1 was identified for its role in mouse mammary tumorigenesis, there is no direct link between Wnt signaling and human breast cancer. However, some of the downstream components of the Wnt pathway, specifically the APC and beta-catenin genes, have been implicated in other forms of human cancer, such as colon cancer.

I hope you find this information useful. Unfortunately, we do not know much about the roles of frizzled genes outside of Wnt signaling, and there are not yet any published studies of frizzled gene knockouts in the mouse. But…stay tuned! This is certainly an area of very active research. I have listed some review articles below. These contain more detailed information than I have given here, as well as several references for specific research articles. In addition, I strongly urge you to check out the Wnt homepage. This has lots of good stuff, especially regarding Wnt signal transduction.

Please feel free to email me if you need anything I have discussed clarified or if you have any further questions!

Nikki
nmdavis@fas.harvard.edu

Dierick, H. and Bejsovec, A. 1999. Cellular mechanisms of wingless/Wnt signal transduction. Current Topics in Developmental Biology 43:153-190.

Dale, T. 1998. Signal transduction by the Wnt family of ligands. Biochemical Journal 329:209-223. (I found this review with online access.)

Wodarz, A and Nusse, R. 1998. Mechanisms of Wnt signaling in development. Annual Review in Cell and Developmental Biology 14:59-88.

Cadigan, K. M. and Nusse, R. 1997. Wnt signaling: a common theme in animal development. Genes and Development 11:3286-3305.