CHARGE syndrome is a multiple congenital anomaly disorder that leads to life-threatening birth defects, such as choanal atresia and cardiac malformations as well as multiple sensory impairments, that affect hearing, vision, olfaction and balance. CHARGE is caused by heterozygous mutations in CHD7, which encodes an ATP-dependent chromatin remodeling enzyme. Identification of the mechanisms underlying neurological and sensory defects in CHARGE is a first step toward developing treatments for CHARGE individuals. Here, we used mouse models of Chd7 deficiency to explore the function of CHD7 in the development of the subventricular zone (SVZ) neural stem cell niche and inner ear, structures that are important for olfactory bulb neurogenesis and hearing and balance, respectively. We found that loss of Chd7 results in cell-autonomous proliferative, neurogenic and self-renewal defects in the perinatal and mature mouse SVZ stem cell niche. Modulation of retinoic acid (RA) signaling prevented in vivo inner ear and in vitro neural stem cell defects caused by Chd7 deficiency. Our findings demonstrate critical, cooperative roles for RA and CHD7 in SVZ neural stem cell function and inner ear development, suggesting that altered RA signaling may be an effective method for treating Chd7 deficiency.

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2 (MMPI-2) is frequently used to evaluate parenting capacity in cases of child abuse and neglect. This study examined MMPI-2 profiles of 59 males and 217 females who completed the test as part of a parenting capacity evaluation following substantiated allegations of child abuse or neglect. After removing 46 (16.7%) invalid profiles, 230 profiles remained. Of these, 119 (52.7%) had T scores on L (Lie) that were at or above 70, indicating a high frequency of underreporting. Mean T scores on the clinical, restructured clinical (RC), content, and PSY-5 scales were all below 65, and 62 (27.0%) profiles contained no elevations (Ն65T) on any of these scales. Elevations on the K-corrected clinical scales were more common than elevations on the other scales. The most commonly elevated scales were RC6, clinical scales 4, 8, 9, 1, 6, 5, and non-K-corrected scale 4. The least frequently elevated scales were ANG, RC9, OBS, and DISC. Multivariate Analyses of Variance (MANOVA) comparing cases with L Ͻ 70T and L Ն 70T showed that elevated scores on L had the greatest effect on the content scales, followed by the RC scales, PSY-5 scales, and the clinical scales without the K-correction. Least affected by elevations on L were the K-corrected clinical scales. The study suggests that efforts to present oneself in a favorable light suppress scores on the MMPI-2 scales to different degrees and that the K-correction is helpful in mitigating the effects of underreporting. Public Significance StatementAlthough the MMPI-2 is frequently used to evaluate parenting capacity in cases of child abuse and neglect, underreporting of problems is common in these samples. This study found that scores on the K-corrected clinical scales were less likely to be suppressed by underreporting than the scores on the non-K-corrected clinical scales, RC scales, content scales or PSY-5 scales.

Summary Proper morphogenesis of inner ear semicircular canals requires precise regulation of cellular proliferation, epithelial-to-mesenchymal transition, and fusion of epithelial plates. Epigenetic regulation of these processes is not well understood, but is likely to involve chromatin remodeling enzymes. CHD7 is a chromodomain-containing, ATP dependent helicase protein that is highly expressed in the developing ear and is required for semicircular canal development in both humans and mice. Here we report that mice with heterozygous loss of Chd7 function exhibit delayed semicircular canal genesis, delayed Netrin1 expression and disrupted expression of genes that are critical for semicircular canal formation (Bmp2, Bmp4, Msx1 and Fgf10). Complete loss of Chd7 results in aplasia of the semicircular canals and sensory vestibular organs, with reduced or absent expression of Otx1, Hmx3, Jagged1, Lmo4, Msx1 and Sox2. Our results suggest that Chd7 may have critical selector gene functions during inner ear morphogenesis. Detailed analysis of the epigenetic modifications underlying these gene expression changes should provide insights into semicircular canal development and help in the design of therapies for individuals with inner ear malformations.