Regulating Hox genes

Abstract

These two papers address the regulation of Hox gene expression in the mouse embryo. Previous work has shown that Fgfr1 null mutations disrupt gastrulation, probably via an effect on cell movement. Partenen et al.1 Partenen J. et al. Opposite phenotypes of hypomorphic and Y766 phosphorylation site mutations reveal a function for Fgfr1 in anteroposterior patterning of mouse embryos. Genes Dev. 1998; 12: 2322-2344 Google Scholar have created a series of Fgfr1 alleles leading to less severe phenotypes, which allow them to dissect a potential role for FGF in patterning the anteroposterior (A–P) axis. Hypomorphic mutations, which reduce the level of Fgfr1 transcription, produce posterior truncation of the embryo and homeotic transformations of the vertebrae similar to those seen in certain Hox gene knockouts. This led them to analyse the effect on Hox expression, and they show that the mesoderm expression of Hoxd4, Hoxb4 and Hoxb9 is altered in a manner consistent with the observed vertebral transformations. Hoxd13 expression is also reduced in the limb buds, consistent with defects in distal limb structures. FGF signalling is believed to be transduced through Ras–MAP kinase and PLCγ pathways. Tyrosine 766 of FGFR1 is an autophosphorylation site that is implicated in transduction via PLCγ. Mutation of Y766 produced vertebral transformations in the opposite direction to those caused by hypomorphic mutations, suggesting that this site is normally involved in repression of ligand-dependent FGFR1 function. It is possible that these FGFR1 mutations affect Hox gene expression by altering cell migration or proliferation. Such alterations are not, however, observed in all mutant alleles, suggesting a more direct involvement of FGF in A–P patterning. One possibility is that FGF alters the expression of Cdx genes, vertebrate homologues of Drosophila caudal. Charité et al.2 Charité J. et al. Transducing positional information to the Hox genes: critical interaction of cdx gene products with position-sensitive regulatory elements. DeveIopment. 1998; 125: 4349-4358 PubMed Google Scholar have identified CDX-binding sites within an upstream regulatory element that can drive regionally restricted expression from the Hoxb8 promoter. A subfragment containing four CDX-binding sites can partially reproduce this expression pattern, and mutation of the sites abolishes its effect. They show that factors in E8.5 embryos that bind these sites are present in an A–P gradient, consistent with the expression pattern of Cdx1, -2 and -4. Supershift data also suggest that these factors are CDX proteins. Ectopic expression of Cdx4 alters the expression pattern of reporters driven by the CDX-binding element, and of endogenous Hoxb8. These results suggest that, unlike Drosophila caudal, vertebrate CDX factors are directly involved in establishing the early expression of Hox genes. Although Partenen et al.1 Partenen J. et al. Opposite phenotypes of hypomorphic and Y766 phosphorylation site mutations reveal a function for Fgfr1 in anteroposterior patterning of mouse embryos. Genes Dev. 1998; 12: 2322-2344 Google Scholar could not detect significant changes in the expression of Cdx1 and -4 in embryos carrying a hypomorphic FGFR1 mutation, they did not rule out their involvement in FGF-mediated regulation of Hox gene expression, as the dynamic pattern of Cdx expression makes it hard to determine whether they are affected.