CHARGE is a multiple congenital anomaly disorder and a common cause of pubertal defects, olfactory dysfunction, growth delays, deaf-blindness, balance disorders and congenital heart malformations. Mutations in CHD7, the gene encoding chromodomain helicase DNA binding protein 7, are present in 60-80% of individuals with the CHARGE syndrome. Mutations in CHD7 have also been reported in the Kallmann syndrome (olfactory dysfunction, delayed puberty and hypogonadotropic hypogonadism). CHD7 is a positive regulator of neural stem cell proliferation and olfactory sensory neuron formation in the olfactory epithelium, suggesting that the loss of CHD7 might also disrupt development of other neural populations. Here we report that female Chd7(Gt/+) mice have delays in vaginal opening and estrus onset, and erratic estrus cycles. Chd7(Gt/+) mice also have decreased circulating levels of luteinizing hormone and follicle-stimulating hormone but apparently normal responsiveness to gonadotropin-releasing hormone (GnRH) agonist and antagonist treatment. GnRH neurons in the adult Chd7(Gt/+) hypothalamus and embryonic nasal region are diminished, and there is decreased cellular proliferation in the embryonic olfactory placode. Expression levels of GnRH1 and Otx2 in the hypothalamus and GnRHR in the pituitary are significantly reduced in adult Chd7(Gt/+) mice. Additionally, Chd7 mutant embryos have CHD7 dosage-dependent reductions in expression levels of Fgfr1, Bmp4 and Otx2 in the olfactory placode. Together, these data suggest that CHD7 has critical roles in the development and maintenance of GnRH neurons for regulating puberty and reproduction.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140819 | PMC |
| http://dx.doi.org/10.1093/hmg/ddr216 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Loss of the chromatin remodeler CHD7 impacts glial cells and myelination in the mouse cochlear spiral ganglion.
Hear Res
December 2022
Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA. Electronic address:
CHARGE syndrome is a multiple anomaly developmental disorder characterized by a variety of sensory deficits, including sensorineural hearing loss of unknown etiology. Most cases of CHARGE are caused by heterozygous pathogenic variants in CHD7, the gene encoding Chromodomain DNA-binding Protein 7 (CHD7), a chromatin remodeler important for the development of neurons and glial cells. Previous studies in the Chd7 mouse model of CHARGE syndrome showed substantial neuron loss in the early stages of the developing inner ear that are compensated for by mid-gestation.
View Article and Find Full Text PDFThe chromatin remodeling protein CHD7, mutated in CHARGE syndrome, is necessary for proper craniofacial and tracheal development.
Dev Dyn
September 2014
Department of Human Genetics, The University of Michigan, Ann Arbor, Michigan; The Medical School, The University of Michigan, Ann Arbor, Michigan; Medical Scientist Training Program, The University of Michigan, Ann Arbor, Michigan.
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.
View Article and Find Full Text PDFMature middle and inner ears express Chd7 and exhibit distinctive pathologies in a mouse model of CHARGE syndrome.
Hear Res
December 2011
Department of Pediatrics, 3520A MSRB I, University of Michigan, Ann Arbor, MI 48109-5652, USA.
Heterozygous mutations in the gene encoding chromodomain-DNA-binding-protein 7 (CHD7) cause CHARGE syndrome, a multiple anomaly condition which includes vestibular dysfunction and hearing loss. Mice with heterozygous Chd7 mutations exhibit semicircular canal dysgenesis and abnormal inner ear neurogenesis, and are an excellent model of CHARGE syndrome. Here we characterized Chd7 expression in mature middle and inner ears, analyzed morphological features of mutant ears and tested whether Chd7 mutant mice have altered responses to noise exposure and correlated those responses to inner and middle ear structure.
View Article and Find Full Text PDFReproductive dysfunction and decreased GnRH neurogenesis in a mouse model of CHARGE syndrome.
Hum Mol Genet
August 2011
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109-5652, USA.
CHARGE is a multiple congenital anomaly disorder and a common cause of pubertal defects, olfactory dysfunction, growth delays, deaf-blindness, balance disorders and congenital heart malformations. Mutations in CHD7, the gene encoding chromodomain helicase DNA binding protein 7, are present in 60-80% of individuals with the CHARGE syndrome. Mutations in CHD7 have also been reported in the Kallmann syndrome (olfactory dysfunction, delayed puberty and hypogonadotropic hypogonadism).
View Article and Find Full Text PDFDefects in neural stem cell proliferation and olfaction in Chd7 deficient mice indicate a mechanism for hyposmia in human CHARGE syndrome.
Hum Mol Genet
June 2009
Department of Human Genetics, University of Michigan Medical Center, 3520A Medical Science Research Building I, Ann Arbor, MI 48109-5652, USA.
Mutations in CHD7, a chromodomain gene, are present in a majority of individuals with CHARGE syndrome, a multiple anomaly disorder characterized by ocular Coloboma, Heart defects, Atresia of the choanae, Retarded growth and development, Genital hypoplasia and Ear anomalies. The clinical features of CHARGE syndrome are highly variable and incompletely penetrant. Olfactory dysfunction is a common feature in CHARGE syndrome and has been potentially linked to primary olfactory bulb defects, but no data confirming this mechanistic link have been reported.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!