title: Loss of Iroquois homeobox transcription factors 3 and 5 in osteoblasts disrupts cranial mineralization.
abstract: Cranial malformations are a significant cause of perinatal morbidity and mortality. Iroquois homeobox transcription factors (IRX) are expressed early in bone tissue formation and facilitate patterning and mineralization of the skeleton. Mice lacking Irx5 appear grossly normal, suggesting that redundancy within the Iroquois family. However, global loss of both Irx3 and Irx5 in mice leads to significant skeletal malformations and embryonic lethality from cardiac defects. Here, we study the bone-specific functions of Irx3 and Irx5 using Osx-Cre to drive osteoblast lineage-specific deletion of Irx3 in Irx5(-/-) mice. Although we found that the Osx-Cre transgene alone could also affect craniofacial mineralization, newborn Irx3 (flox/flox) /Irx5(-/-)/Osx-Cre (+) mice displayed additional mineralization defects in parietal, interparietal, and frontal bones with enlarged sutures and reduced calvarial expression of osteogenic genes. Newborn endochondral long bones were largely unaffected, but we observed marked reductions in 3-4-week old bone mineral content of Irx3 (flox/flox) /Irx5(-/-)/Osx-Cre (+) mice. Our findings indicate that IRX3 and IRX5 can work together to regulate mineralization of specific cranial bones. Our results also provide insight into the causes of the skeletal changes and mineralization defects seen in Hamamy syndrome patients carrying mutations in IRX5.
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, Institute for Human Genetics, Program in Craniofacial Biology, University of California, San Francisco, San Francisco, CA 94143-0794, USA.
authors.forename: Corey J
authors.initials: CJ
authors.lastname: Cain
authors.affiliation: Inserm, UMR 1087, l'institut du thorax, Nantes, France; CNRS, UMR 6291, Nantes, France; Université de Nantes, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Gaborit
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, Institute for Human Genetics, Program in Craniofacial Biology, University of California, San Francisco, San Francisco, CA 94143-0794, USA.
authors.forename: Wint
authors.initials: W
authors.lastname: Lwin
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, Institute for Human Genetics, Program in Craniofacial Biology, University of California, San Francisco, San Francisco, CA 94143-0794, USA.
authors.forename: Emilie
authors.initials: E
authors.lastname: Barruet
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, Institute for Human Genetics, Program in Craniofacial Biology, University of California, San Francisco, San Francisco, CA 94143-0794, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Ho
authors.affiliation: Human Embryology and Genetics Laboratory, Institute of Medical Biology, ASTAR, Singapore 138648, Singapore.
authors.forename: Carine
authors.initials: C
authors.lastname: Bonnard
authors.affiliation: Department of Genetic Medicine and Development, Geneva University, Geneva 1211, Switzerland.
authors.forename: Hanan
authors.initials: H
authors.lastname: Hamamy
authors.affiliation: Human Embryology and Genetics Laboratory, Institute of Medical Biology, ASTAR, Singapore 138648, Singapore.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Shboul
authors.affiliation: Human Embryology and Genetics Laboratory, Institute of Medical Biology, ASTAR, Singapore 138648, Singapore.
authors.forename: Bruno
authors.initials: B
authors.lastname: Reversade
authors.affiliation: Medical Genetics Department, Koc University School of Medicine, Rumelifeneri Yolu, Sarıyer, Istanbul 34450, Turkey; Medical Genetics Department, Istanbul Medical Faculty, Istanbul University Topkapi, Fatih, 34093 lstanbul, Turkey.
authors.forename: Hülya
authors.initials: H
authors.lastname: Kayserili
authors.affiliation: Gladstone Institute for Cardiovascular Disease, San Francisco, CA 94158, USA; Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Benoit G
authors.initials: BG
authors.lastname: Bruneau
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, Institute for Human Genetics, Program in Craniofacial Biology, University of California, San Francisco, San Francisco, CA 94143-0794, USA.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Hsiao
keywords: Osteoblast mineralization; Osteoclast/osteoblast biology; Osteoporosis