Mutations in IRX5 impair craniofacial development and germ cell migration via SDF1

Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
Nature Genetics (Impact Factor: 29.35). 05/2012; 44(6):709-13. DOI: 10.1038/ng.2259
Source: PubMed


Using homozygosity mapping and locus resequencing, we found that alterations in the homeodomain of the IRX5 transcription factor cause a recessive congenital disorder affecting face, brain, blood, heart, bone and gonad development. We found through in vivo modeling in Xenopus laevis embryos that Irx5 modulates the migration of progenitor cell populations in branchial arches and gonads by repressing Sdf1. We further found that transcriptional control by Irx5 is modulated by direct protein-protein interaction with two GATA zinc-finger proteins, GATA3 and TRPS1; disruptions of these proteins also cause craniofacial dysmorphisms. Our findings suggest that IRX proteins integrate combinatorial transcriptional inputs to regulate key signaling molecules involved in the ontogeny of multiple organs during embryogenesis and homeostasis.

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Available from: Bruno Reversade, Feb 15, 2014
    • "We further note that these studies illustrate that different animal model systems can often complement each other in analyzing the consequences of a given mutation. These types of studies are the first glimpse presaging an exciting new period in craniofacial research – one in which the identification of candidate human mutations resulting from genome-wide sequence analysis can be allied with the new gene-editing approaches and available mutant resources in animal models for the rapid expansion of our understanding and ap- pre Q10 ciation of this fascinating developmental system.Araki et al. (2004), Ashe et al. (2012), Bajpai et al. (2010), Barbaric et al. (2008), Bonnard et al. (2012), Bourgeois et al. (1998), Bush et al. (2004), Feng et al. (2008), Ghoumid et al. (2013), Hernandez-Porras et al. (2014), Hu et al. (2015,Hu et al. (2014), Momb et al. (2013), Nissen et al. (2006), Ueda et al., (2006), Wang et al. (2005Yanagisawa et al. (2003) andYin et al. (2008). "
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