Loss of Iroquois homeobox transcription factors 3 and 5 in osteoblasts disrupts cranial mineralization
Corey J. Cain,
Nathalie Gaborit,
Wint Lwin,
Emilie Barruet,
Samantha Ho,
Carine Bonnard,
Hanan Hamamy,
Mohammad Shboul,
Bruno Reversade,
Hülya Kayserili,
Benoit G. Bruneau,
Edward C. Hsiao
Affiliations
Corey J. Cain
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
Nathalie Gaborit
Inserm, UMR 1087, l’institut du thorax, Nantes, France; CNRS, UMR 6291, Nantes, France; Université de Nantes, France
Wint Lwin
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
Emilie Barruet
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
Samantha Ho
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
Carine Bonnard
Human Embryology and Genetics Laboratory, Institute of Medical Biology, A*STAR, Singapore 138648, Singapore
Hanan Hamamy
Department of Genetic Medicine and Development, Geneva University, Geneva 1211, Switzerland
Mohammad Shboul
Human Embryology and Genetics Laboratory, Institute of Medical Biology, A*STAR, Singapore 138648, Singapore
Bruno Reversade
Human Embryology and Genetics Laboratory, Institute of Medical Biology, A*STAR, Singapore 138648, Singapore
Hülya Kayserili
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
Benoit G. Bruneau
Gladstone Institute for Cardiovascular Disease, San Francisco, CA 94158, USA; Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA
Edward C. Hsiao
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; Corresponding author at: University of California, San Francisco, 513 Parnassus Ave., HSE901G, San Francisco, CA 94143-0794, USA.
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 Irx3flox/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 Irx3flox/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. Keywords: Osteoclast/osteoblast biology, Osteoporosis, Osteoblast mineralization
