Control of cranial neural crest fate decision by Hox genes
Lead Research Organisation:
University of Manchester
Department Name: Dentistry
Abstract
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.
Technical Summary
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.
Organisations
People |
ORCID iD |
Nicoletta Bobola (Principal Investigator) |
Publications
Amin S
(2014)
Chromatin immunoprecipitation and chromatin immunoprecipitation with massively parallel sequencing on mouse embryonic tissue.
in Methods in molecular biology (Clifton, N.J.)
Amin S
(2015)
Hoxa2 selectively enhances Meis binding to change a branchial arch ground state.
in Developmental cell
Anderson M
(2013)
Differential distribution of the Ca (2+) regulator Pcp4 in the branchial arches is regulated by Hoxa2.
in PloS one
Donaldson IJ
(2012)
Genome-wide occupancy links Hoxa2 to Wnt-ß-catenin signaling in mouse embryonic development.
in Nucleic acids research
He G
(2010)
Inactivation of Six2 in mouse identifies a novel genetic mechanism controlling development and growth of the cranial base.
in Developmental biology
Kirilenko P
(2011)
Transient activation of meox1 is an early component of the gene regulatory network downstream of hoxa2.
in Molecular and cellular biology
Minoux M
(2013)
Mouse Hoxa2 mutations provide a model for microtia and auricle duplication.
in Development (Cambridge, England)
Tavella S
(2010)
Expressing Hoxa2 across the entire endochondral skeleton alters the shape of the skeletal template in a spatially restricted fashion.
in Differentiation; research in biological diversity
Description | The cranial neural crest is a cell population that is unique to vertebrate embryos and gives rise to many derivatives, including the craniofacial skeleton and the heart circulation. Correct development of neural crest-derived organs and tissues is controlled by the large family of Hox proteins. Despite the fundamental importance of Hox proteins in embryogenesis, and also cancer and cell regeneration, the events controlled by Hox proteins are poorly understood. Exploiting high-throughput expression analysis and next generation sequencing, a recent technical development in today's biology, this research has identified the genes under direct control of the Hox protein Hoxa2 in the cranial neural crest. Our list of Hoxa2 genomic targets has been, to the best of our knowledge, the first genome-wide list of Hox targets in vertebrate in vivo. As such, it offers an extremely valuable resource to the large community of researchers investigating Hox function in vertebrate development, homeostasis and disease. |
Exploitation Route | The comprehensive identification of Hox-regulated genes offers an extremely valuable resource to the large community of researchers investigating Hox function in vertebrate development, homeostasis and disease. The high-throughput data generated, including ChIP-seq and microarrays have been deposited in ArrayExpress (EBI). Craniofacial abnormalities, which account for one third of all congenital birth defects, are the most common cranial neural crest -related developmental defects. The identification of Hoxa2-regulated genes in the cranial neural crest is important for understanding the causes of birth defects and providing new strategies for their prevention and cures. |
Sectors | Education Healthcare |
Description | The findings have resulted in 7 manuscripts and five large-scale datasets, which are publicly available. The results generated in the project have been used to understand the causes of microtia, a genetic condition associated to deafness. In addition findings and datasets generated in this research have been exploited by other groups to develop and validate new bioinformatics tools. |
First Year Of Impact | 2012 |
Sector | Healthcare,Other |