Aortic arch artery patterning defects account for approximately 20% of congenital cardiovascular malformations and are observed frequently in velocardiofacial syndrome (VCFS). In the current study, we screened for chromosome rearrangements in patients suspected of VCFS, but who lacked a 22q11 deletion or TBX1 mutation. One individual displayed hemizygous CHD7, which encodes a chromodomain protein. CHD7 haploinsufficiency is the major cause of coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, and ear anomalies/deafness (CHARGE) syndrome, but this patient lacked the major diagnostic features of coloboma and choanal atresia. Because a subset of CHARGE cases also display 22q11 deletions, we explored the embryological relationship between CHARGE and VCSF using mouse models. The hallmark of Tbx1 haploinsufficiency is hypo/aplasia of the fourth pharyngeal arch artery (PAA) at E10.5. Identical malformations were observed in Chd7 heterozygotes, with resulting aortic arch interruption at later stages. Other than Tbx1, Chd7 is the only gene reported to affect fourth PAA development by haploinsufficiency. Moreover, Tbx1 +/-;Chd7 +/-double heterozygotes demonstrated a synergistic interaction during fourth PAA, thymus, and ear morphogenesis. We could not rescue PAA morphogenesis by restoring neural crest Chd7 expression. Rather, biallelic expression of Chd7 and Tbx1 in the pharyngeal ectoderm was required for normal PAA development.
CHARGE syndrome is characterised by coloboma, heart defects including Tetralogy of Fallot, choanal atresia, retarded growth and development, genital and ear abnormalities. Deletion or mutation of chromodomain protein CHD7 is the major cause of this syndrome. Di George syndrome is frequently associated with a deletion of 22q11.2 and haploinsufficiency of T-box transcription factor TBX1 causes a number of symptoms including great vessel defects particularly of the outflow tract and aortic arch.Such cardiovascular malformations arise from defective remodelling of the pharyngeal arch arteries (PAA). The significant phenotypic overlap of these disorders and the fact that Chd7 is the only gene other than Tbx1 reported to affect 4th PAA development by haploinsufficiency, led us to investigate the embryological relationship between the two syndromes using mouse models.Hypo/aplasia was observed in both Tbx1 and Chd7 heterozygote mice at E10.5 with resulting interruption of the aortic arch observed at later stages. Double heterozygous mice displayed a synergistic interaction for this phenotype. Restoration of Chd7 in the neural crest or mesoderm did not rescue PAA morphogenesis, however dizygous expression of Chd7 and Tbx1 in the pharyngeal ectoderm was required for normal PAA development.We are studying the effects of environmentally induced disruptions in the nervous system development using zebrafish (Danio rerio) as a model. Alcohol is an environmental teratogen that, when consumed during pregnancy, causes craniofacial malformations as well as a spectrum of neurological and behavioral disorders, known as Fetal Alcohol Syndrome (FAS). Craniofacial structures arise from cranial neural crest (CNC); these progenitors share a common border with the cells of the olfactory placode (OP) field during development in the zebrafish. We propose that olfactory system's development might also be affected by teratogens. We will focus on the effects on OP and CNC progenitor migration. We incubated zebrafish embryos with Ethanol or Pisco and analyzed expression of chemokine cxcr12a and its receptor cxcr4b, genes essential in OP development. invivo CNC migration was studied using sox10-GFP embryos. For morphological analysis, death, malformation and cell death were scored. Embryos' ethanol tissue concentration was also assessed.Our results suggest that alcohol affects OP progenitor organization, CNC migration, and enhances cell death. Also, alcohol produces craniofacial abnormalities very similar to the malformations seen in FAS patients.Another agent we are testing is the antiparasitic Ivermectin.So far we have found that embryos incubated for 45 h (10-500 ng/L) showed impaired movements.This research will allow us to develop an ''EcoDevo'' system model for assessing how teratogents affect nervous system development.Hypohidrotic ectodermal dysplasia (HED) is a disorder characterized by defective ectodermal organ development. This includes the salivary glands (SG), which have an important role in lubricating the oral cavity. In humans an...
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