Control of cranial neural crest fate decision by Hox genes

Hox genes control morphogenesis along the antero-posterior axis of the developing embryo. The encoded proteins act as transcription factors, but their target genes are mostly unknown in vertebrates. This proposal is aimed at the identification of the genes directly regulated by Hoxa2 in the control of the differentiation of the cranial neural crest, a transient cell population of the vertebrate embryo. These embryonic cells can give rise to many derivatives, but their capacity to form skeletal tissues is inhibited by Hox genes and in particular by Hoxa2. The key to the identification of the genes controlled by Hoxa2 in the differentiation of the cranial neural crest will be the generation and the analysis of mutant mice with inducible expression of Hoxa2 in the cranial neural crest. This model system is designed to conclusively characterize the immediate events downstream of Hoxa2. The results obtained will give insights into how Hox genes regulate morphogenesis in the vertebrate embryo and help to understand the mechanisms that govern the formation of the facial skeleton. The work will be carried at the University of Manchester.

Hox genes regulate morphogenesis along the antero-posterior axis of the developing embryo. The encoded proteins act as transcription factors, but their target genes in vertebrates remain mostly unknown. This proposal describes the generation and the analysis of a new experimental system to effectively approach the long-standing problem of Hox targets in vertebrates. The system is designed to identify the genes directly regulated by Hoxa2 in the control of cranial neural crest differentiation in the mouse. It is based on the ectopic expression of Hoxa2 in the anterior cranial neural crest, achieved by knock-in of Hoxa2 into the ROSA26 locus and its consequent transcription by Wnt1-Cre-mediated recombination. Expression profiling of the gain of function mutant is expected to complement the large-scale analysis of the Hoxa2 loss of function mutant in the identification of the genes regulated by Hoxa2. The integration in the genome of a tagged version of Hoxa2 will provide Chromatin Immuno-Precipitation (ChIP) as the assay of choice to conclusively demonstrate the direct interaction of Hoxa2 with the chromatin of its target genes in vivo. The results obtained will give insights into how Hox genes regulate morphogenesis in the vertebrate embryo and improve our understanding of the mechanisms that govern the formation of the facial skeleton.