Reproductive dysfunction and decreased GnRH neurogenesis in a mouse model of CHARGE syndrome

• Published in: Human molecular genetics Vol. 20; no. 16; pp. 3138 - 3150
• Main Authors: Layman, Wanda S., Hurd, Elizabeth A., Martin, Donna M.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 15.08.2011
• Subjects: Animals; Biological and medical sciences; Cell Count; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Cell Proliferation; CHARGE syndrome; CHARGE Syndrome - pathology; CHARGE Syndrome - physiopathology; Complex syndromes; Congenital defects; Disease Models, Animal; DNA helicase; DNA-binding protein; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - metabolism; Embryo, Mammalian - metabolism; Embryo, Mammalian - pathology; Embryos; Estrous Cycle - metabolism; Estrus; Female; Fibroblast growth factor receptor 1; Fundamental and applied biological sciences. Psychology; Gene Dosage - genetics; Gene Expression Regulation, Developmental; Genetics of eukaryotes. Biological and molecular evolution; Gonadotropin-releasing hormone; Gonadotropin-Releasing Hormone - agonists; Gonadotropin-Releasing Hormone - blood; Gonadotropin-Releasing Hormone - metabolism; Hypothalamus - embryology; Hypothalamus - metabolism; Medical genetics; Medical sciences; Mice; Molecular and cellular biology; Mutation; Neurogenesis; Neurons - metabolism; Neurons - pathology; Nose - embryology; Nose - pathology; Olfaction; Olfactory Bulb - embryology; Olfactory Bulb - pathology; olfactory placode; Olfactory receptor neurons; Otx2 protein; Pituitary; Pituitary Gland - embryology; Pituitary Gland - metabolism; Puberty; Puberty - metabolism; Reproduction; Reproduction - physiology; Sensory neurons; Vagina; Animal model; Nervous system diseases; Urinary system disease; Rodentia; Cardiovascular disease; Neurogenesis; Vertebrata; Reproduction; Mammalia; Mouse; Dysfunction; CHARGE syndrome; ENT disease; Genetics; Complex syndrome
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddr216

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 Chd7Gt/+ mice have delays in vaginal opening and estrus onset, and erratic estrus cycles. Chd7Gt/+ 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 Chd7Gt/+ 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 Chd7Gt/+ 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.