FZD4 Research Articles

Mouse fzd4 maps within a region of chromosome 7 important for thymus and cardiac development.

The cardiac neural crest (CNC) plays a central role in development of the thymus gland and cardiovascular system. Through morphological and histological characterization of embryos homozygous for the Del(7)Tyr(c-112K) and Del(7)Tyr(c-3H) albino deletions, we identified abnormalities that are consistent with aberrant development of tissues requiring CNC contributions. The defects include incompletely penetrant heart and great vessel patterning defects and hypoplastic thymus glands. The CNC phenotype is complemented by the partially overlapping deletion Del(7)Tyr(c-23DVT). Combined, these results suggest that a functional region necessary for development of CNC derived tissues is located between the Del(7)Tyr(c-23DVT) and Del(7)Tyr(c-112K) distal deletion breakpoints. This interval encompasses a functional region previously identified as important for juvenile survival (juvenile development and fertility, jdf). Using deletion mapping, we localized the Frizzled4 (Fzd4) gene to the jdf/thymus and cardiac development intervals.

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

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.