The chromatin remodeling protein CHD7, mutated in CHARGE syndrome, is necessary for proper craniofacial and tracheal development

Background: Heterozygous mutations in the chromatin remodeling gene CHD7 cause CHARGE syndrome, a developmental disorder with variable craniofacial dysmorphisms and respiratory difficulties. The molecular etiologies of these malformations are not well understood. Homozygous Chd7 null mice die by E11, whereas Chd7 Gt/+ heterozygous null mice are a viable and excellent model of CHARGE. We explored skeletal phenotypes in Chd7 Gt/+ and Chd7 conditional knockout mice, using Foxg1‐Cre to delete Chd7 ( Foxg1 ‐CKO) in the developing eye, ear, nose, pharyngeal pouch, forebrain, and gut and Wnt1‐Cre ( Wnt1 ‐CKO) to delete Chd7 in migrating neural crest cells. Results: Foxg1 ‐CKO mice exhibited postnatal respiratory distress and death, dysplasia of the eye, concha, and frontal bone, hypoplastic maxillary shelves and nasal epithelia, and reduced tracheal rings. Wnt1‐ CKO mice exhibited frontal and occipital bone dysplasia, hypoplasia of the maxillary shelves and mandible, and cleft palate. In contrast, heterozygous Chd7 Gt/+ mice had apparently normal skeletal development. Conclusions: Conditional deletion of Chd7 in ectodermal and endodermal derivatives ( Foxg1‐Cre ) or migrating neural crest cells ( Wnt1‐Cre ) results in varied and more severe craniofacial defects than in Chd7 Gt/+ mice. These studies indicate that CHD7 has an important, dosage‐dependent role in development of several different craniofacial tissues. Developmental Dynamics 243:1055–1066, 2014 . © 2014 The Authors Developmental Dynamics published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists. Key findings: Chd7 is necessary in craniofacial ectodermal, endodermal, and neural crest cells. Loss of Chd7 in mice results in upper and lower respiratory tract anomalies which mimic human CHARGE syndrome. Chd7 is important for proper development of neural crest‐derived mesenchymal tissues contributing to bone and cartilage. Loss of Wnt1Cre‐mediated Chd7 in neural crest cells does not result in heart defects. Foxg1Cre‐mediated deletion of Chd7 leads to severe microphthalmia.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108278/1/dvdy24156.pd

The chromatin remodeling protein CHD7, mutated in CHARGE syndrome, is necessary for proper craniofacial and tracheal development

Background: Heterozygous mutations in the chromatin remodeling gene CHD7 cause CHARGE syndrome, a developmental disorder with variable craniofacial dysmorphisms and respiratory difficulties. The molecular etiologies of these malformations are not well understood. Homozygous Chd7 null mice die by E11, whereas Chd7 Gt/+ heterozygous null mice are a viable and excellent model of CHARGE. We explored skeletal phenotypes in Chd7 Gt/+ and Chd7 conditional knockout mice, using Foxg1‐Cre to delete Chd7 ( Foxg1 ‐CKO) in the developing eye, ear, nose, pharyngeal pouch, forebrain, and gut and Wnt1‐Cre ( Wnt1 ‐CKO) to delete Chd7 in migrating neural crest cells. Results: Foxg1 ‐CKO mice exhibited postnatal respiratory distress and death, dysplasia of the eye, concha, and frontal bone, hypoplastic maxillary shelves and nasal epithelia, and reduced tracheal rings. Wnt1‐ CKO mice exhibited frontal and occipital bone dysplasia, hypoplasia of the maxillary shelves and mandible, and cleft palate. In contrast, heterozygous Chd7 Gt/+ mice had apparently normal skeletal development. Conclusions: Conditional deletion of Chd7 in ectodermal and endodermal derivatives ( Foxg1‐Cre ) or migrating neural crest cells ( Wnt1‐Cre ) results in varied and more severe craniofacial defects than in Chd7 Gt/+ mice. These studies indicate that CHD7 has an important, dosage‐dependent role in development of several different craniofacial tissues. Developmental Dynamics 243:1055–1066, 2014 . © 2014 The Authors Developmental Dynamics published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists. Key findings: Chd7 is necessary in craniofacial ectodermal, endodermal, and neural crest cells. Loss of Chd7 in mice results in upper and lower respiratory tract anomalies which mimic human CHARGE syndrome. Chd7 is important for proper development of neural crest‐derived mesenchymal tissues contributing to bone and cartilage. Loss of Wnt1Cre‐mediated Chd7 in neural crest cells does not result in heart defects. Foxg1Cre‐mediated deletion of Chd7 leads to severe microphthalmia.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108278/1/dvdy24156.pd