https://web.stanford.edu/group/nusselab/cgi-bin/wnt/sites/default/files/reviews/Cell%202012%20Clevers.pdf

Wnt/β-catenin signaling and disease.

Wnt proteins are now recognized as one of the major families of developmentally important signaling molecules, with mutations in Wnt genes displaying remarkable phenotypes in the mouse, Caenorhabditis elegans, and Drosophila. Among functions provided by Wnt proteins are such intriguing processes as embryonic induction, the generation of cell polarity, and the specification of cell fate. Until recently, our knowledge of the molecular mechanism of Wnt signaling was very limited, but over the past year, several major gaps have been filled. These include the identification of cell-surface receptors and a novel mechanism of relaying the signal to the cell nucleus. In addition, several components of Wnt signaling are implicated in the genesis of human cancer. These insights have come from different corners of the animal kingdom and have converged on a common pathway. At this junction in this rapidly evolving field, we review our current understanding of Wnt function and signaling mechanisms, doing so in a comparative approach. We have put emphasis on the latest findings, highlighting novelty and underscoring questions that remain. For additional literature, we refer to several previous reviews (McMahon 1992; Nusse and Varmus 1992; Klingensmith and Nusse 1994; Miller and Moon 1996; Moon et al. 1997). We have limited the number of references, particularly in the tables. Fully referenced forms of these tables can be found on the Wnt homepage (http://wwwleland.stanford.edu/∼rnusse/wntwindow.html).

/pdf/wnt-signaling-a-common-theme-in-animal-development-4ifaxai8dj.pdf

Wnt signaling: a common theme in animal development

Wnt genes encode a large family of secreted, cysteine-rich proteins that play key roles as intercellular signaling molecules in development. Genetic studies in Drosophila and Caenorhabditis elegans, ectopic gene expression in Xenopus, and gene knockouts in the mouse have demonstrated the involvement of Wnts in processes as diverse as segmentation, CNS patterning, and control of asymmetric cell divisions. The transduction of Wnt signals between cells proceeds in a complex series of events including post-translational modification and secretion of Wnts, binding to transmembrane receptors, activation of cytoplasmic effectors, and, finally, transcriptional regulation of target genes. Over the past two years our understanding of Wnt signaling has been substantially improved by the identification of Frizzled proteins as cell surface receptors for Wnts and by the finding that beta-catenin, a component downstream of the receptor, can translocate to the nucleus and function as a transcriptional activator. Here we review recent data that have started to unravel the mechanisms of Wnt signaling.

/pdf/mechanisms-of-wnt-signaling-in-development-1prqj8ykgq.pdf

Mechanisms of wnt signaling in development

G protein-coupled receptors (GPCRs) are the largest family of membrane-bound receptors and also the targets of many drugs. Understanding of the functional significance of the wide structural diversity of GPCRs has been aided considerably in recent years by the sequencing of the human genome and by structural studies, and has important implications for the future therapeutic potential of targeting this receptor family. This article aims to provide a comprehensive overview of the five main human GPCR families--Rhodopsin, Secretin, Adhesion, Glutamate and Frizzled/Taste2--with a focus on gene repertoire, general ligand preference, common and unique structural features, and the potential for future drug discovery.

Structural diversity of G protein-coupled receptors and significance for drug discovery

Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits

Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder with multisystemic manifestations caused by heterozygosity for a partial deletion of chromosome band 7q11.23. The breakpoints cluster within regions located approximately 1 cM either side of the elastin (ELN) locus. We have characterized a duplicated region near the common deletion breakpoints, which includes a transcribed gene. The centromeric (C) and telomeric (T) copies are almost identical in the duplicated 3[prime] portions but diverge at their 5[prime]-ends. C-specific 4.3 kb mRNA and T-specific 5.4 kb mRNA are widely expressed in embryonic and adult tissues. The telomeric gene gives rise to several alternatively spliced forms and is deleted in all WBS individuals who have documented ELN deletions. Database searches revealed that this gene encodes BAP-135, a protein phosphorylated by Bruton's tyrosine kinase in B cells, as well as the multifunctional transcription factor TFII-I, hence the gene name GTF2I. The centromeric gene is not deleted in WBS and appears to be a partially truncated expressed pseudogene with no protein product (gene name GTF2IP1). Both loci map to different genomic clone contigs that also contain other deleted and non-deleted loci. A probe from the shared region recognizes a >3 Mb Not I junction fragment that is unique to individuals with the WBS deletion. Therefore, the duplicated region containing GTF2I and GTF2IP1 respectively is located close to the deletion breakpoints and may predispose to unequal meiotic recombination between chromosome 7 homologs and/or to intrachromosomal rearrangements. Hemizygosity for GTF2I may also contribute to the WBS phenotype.

A Duplicated Gene in the Breakpoint Regions of the 7q11.23 Williams-Beuren Syndrome Deletion Encodes the Initiator Binding Protein TFII-I and BAP-135, a Phosphorylation Target of BTK

Williams syndrome (WS) is a developmental disorder with a characteristic personality and cognitive profile that is associated, in most cases, with a 2 Mb deletion of part of chromosome band 7q11.23. By applying CpG island cloning methods to cosmids from the deletion region, we have identified a new gene, called FZD3. Dosage blotting of DNA from 11 WS probands confirmed that it is located within the commonly deleted region. Sequence comparisons revealed that FZD3, encoding a 591 amino acid protein, is a novel member of a seven transmembrane domain receptor family that are mammalian homologs of the Drosophila tissue polarity gene frizzled. FZD3 is expressed predominantly in brain, testis, eye, skeletal muscle and kidney. Recently, frizzled has been identified as the receptor for the wingless (wg) protein in Drosophila. We show that Drosophila as well as human cells, when transfected with FZD3 expression constructs, bind Wg protein. In mouse, the wg homologous Wnt1 gene is involved in early development of a large domain of the central nervous system encompassing much of the midbrain and rostral metencephalon. The potential function of FZD3 in transmitting a Wnt protein signal in the human brain and other tissues suggests that heterozygous deletion of the FZD3 gene could contribute to the WS phenotype.

/pdf/a-novel-human-homologue-of-the-drosophila-frizzled-wnt-onkgh27d8z.pdf

A novel human homologue of the Drosophila frizzled wnt receptor gene binds wingless protein and is in the Williams syndrome deletion at 7q11.23

Characterization and expression pattern of the frizzled gene Fzd9, the mouse homolog of FZD9 which is deleted in Williams-Beuren syndrome.

Williams syndrome (WS) is a developmental disorder with multiple system manifestations, including supraval var aortic stenosis (SVAS), peripheral pulmonic stenosis, connective tissue abnormalities, short stature, characteristic personality profile and cognitive deficits, and variable hypercalcemia in infancy. It is caused by heterozygosity for a chromosomal deletion of part of band 7q11.23 including the elastin locus (ELN). Since disruption of the ELN gene causes autosomal dominant SVAS, it is assumed that ELN haploinsufficiency is responsible for the cardiovascular features of WS. The deletion that extends from the ELN locus in both directions is {ge}200 kb in size, although estimates of {ge}2 Mb are suggested by high-resolution chromosome banding and physical mapping studies. We have searched for additional dosage-sensitive genes within the deletion that may be responsible for the noncardiovascular features. We report here that the gene for replication factor C subunit 2 (RFC2) maps within the WS deletion region and was found to be deleted in all of 18 WS patients studied. The protein product of RFC2 is part of a multimeric complex involved in DNA elongation during replication. 14 refs., 3 figs.

Yu-Ker Wang

Papers

A Duplicated Gene in the Breakpoint Regions of the 7q11.23 Williams-Beuren Syndrome Deletion Encodes the Initiator Binding Protein TFII-I and BAP-135, a Phosphorylation Target of BTK

A novel human homologue of the Drosophila frizzled wnt receptor gene binds wingless protein and is in the Williams syndrome deletion at 7q11.23

Characterization and expression pattern of the frizzled gene Fzd9, the mouse homolog of FZD9 which is deleted in Williams-Beuren syndrome.

The gene for replication factor C subunit 2 (RFC2) is within the 7q11.23 Williams syndrome deletion.

Genes for the CPE receptor (CPETR1) and the human homolog of RVP1 (CPETR2) are localized within the Williams-Beuren syndrome deletion.