Normal tissue development and maintenance requires precise timing and correct localization of gene expression. Several lines of evidence indicate that the chromodomain (CHD) families of proteins are critical regulators of chromatin remodeling and gene expression. In humans, haploinsufficiency for CHD7 causes CHARGE syndrome, a multiple anomaly condition characterized by ocular coloboma, heart defects, atresia of the choanae, retarded growth and development, genital hypoplasia and ear abnormalities including deafness and vestibular disorders. Many patients with CHARGE display Kallmann-like features which include olfactory and endocrine dysfunction. Clinical evidence indicates that mutations in CHD7 lead to pleiotropic developmental defects;however, the mechanisms underlying these defects have not yet been determined. In order to study the role of CHD7 in development, we generated mice carrying a Chd7Gt allele derived from Chd7 deficient gene trapped lacZ reporter embryonic stem cells and recently generated mice with a conditional Chd7 null allele, Chd7flox. Chd7 null mice are embryonic lethal by E11. Chd7Gt/+ mice exhibit features similar to human CHARGE phenotypes, including postnatal growth delay, vestibular dysfunction, and olfactory defects which include olfactory bulb hypoplasia and hyposmia. These data indicate that olfactory dysfunction may primarily result from defects in neural stem cell proliferation and reduced olfactory sensory neurons in the olfactory epithelium. However, defects in neural stem cell proliferation in the sub ventricular zone may also contribute to olfactory bulb defects common in both humans and mice with Chd7 deficiency. Defects in GnRH neuronal migration along olfactory sensory neurons from the nose to the olfactory bulb and ultimately to the hypothalamus are common in Kallmann syndrome, and could also contribute to endocrine defects in Chd7 mutant mice. Further analysis of the Kallmann-like features in Chd7 mutant mice may indicate a functional role for CHD7 in neural development. The long term goal of this research is to determine the role of CHD7 in neural tissues in order to help improve diagnosis and treatment of olfactory and endocrine defects. The global hypothesis is that CHD7 regulates neural stem cell proliferation and neurogenesis in olfactory and endocrine tissue development and maintenance. There are three specific aims: 1) Test the hypothesis that Chd7 is required for maintenance of neural stem cells in the adult subventricular zone. 2) Test the hypothesis that Chd7 is necessary for normal hypothalamic-pituitary signaling in adult mice. 3) Test the hypothesis that Chd7 dosage (ie. Haploid sufficiency versus homozygous loss) causes differential effects on central nervous system neural stem cells.
The results of this research will lead to significant advances in our basic understanding of how CHD7 contributes to olfactory and endocrine tissue development and maintenance. The mechanisms that underlie chromatin remodeling and transcriptional regulation are likely to be critical for establishment and/or maintenance of olfactory and endocrine tissues. These results may also contribute to public health in the development of improved therapies for odorant detection and reproductive dysfunction and related disorders.
| Micucci, Joseph A; Layman, Wanda S; Hurd, Elizabeth A et al. (2014) CHD7 and retinoic acid signaling cooperate to regulate neural stem cell and inner ear development in mouse models of CHARGE syndrome. Hum Mol Genet 23:434-48 |
| Layman, Wanda S; Hurd, Elizabeth A; Martin, Donna M (2011) Reproductive dysfunction and decreased GnRH neurogenesis in a mouse model of CHARGE syndrome. Hum Mol Genet 20:3138-50 |
