22q11 Gene dosage establishes an adaptive range for sonic hedgehog and retinoic acid signaling during early development

GW Institute for Neuroscience and Department of Pharmacology and Physiology, The George Washington University School of Medicine and Health Sciences, Washington DC, USA.
Human Molecular Genetics (Impact Factor: 6.39). 10/2012; 22(2). DOI: 10.1093/hmg/dds429
Source: PubMed


We asked whether key morphogenetic signaling pathways interact with 22q11 gene dosage to modulate the severity of cranial or cardiac anomalies in DiGeorge/22q1Deletion Syndrome (22q11DS). Sonic hedgehog (Shh) and Retinoic Acid (RA) signaling is altered in the brain and heart-clinically significant 22q11DS phenotypic sites-in LgDel mouse embryos, an established 22q11DS model. LgDel embryos treated with cyclopamine, a Shh inhibitor, or carrying mutations in Gli3(Xtj), a Shh signaling effector, have morphogenetic anomalies that are either not seen, or seen at significantly lower frequencies in control or single mutant embryos. Similarly, RA exposure or genetic loss of RA function via heterozygous mutation of the RA synthetic enzyme Raldh2 induces novel cranial anomalies and enhances cardiovascular phenotypes in LgDel but not other genotypes. These changes are not seen in heterozygous Tbx1 mutant embryos-a 22q11 gene thought to explain much of 22q11DS pathogenesis-in which Shh or RA signaling has been similarly modified. Our results suggest that full dosage of 22q11 genes beyond Tbx1 establish an adaptive range for morphogenetic signaling via Shh and RA. When this adaptive range is constricted by diminished dosage of 22q11 genes, embryos are sensitized to otherwise benign changes in Shh and RA signaling. Such sensitization, in the face of environmental or genetic factors that modify Shh or RA signaling, may explain variability in 22q11DS morphogenetic phenotypes.

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    • "It is possible that multi-ligand receptor LRP2 influences different pathways during cardiac development or maybe even plays a yet still unknown key role in connecting pathways such as we know from TBX1 (Garg et al., 2001) which influences both Shh and RA dependent Disease Models & Mechanisms @BULLET DMM @BULLET Advance article signaling (Liao et al., 2008). We know that morphogens like Shh and RA act in parallel with other pathways such as the BMP and nodal pathway, in the regulation of shared target genes (Maynard et al., 2013;Wong et al., 2012). Future studies should unravel the position of Lrp2 in these networks of genes. "
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    ABSTRACT: Background Lipoprotein-related receptor protein 2 (LRP2) is important for the embryonic neural crest and brain development in both mice and humans. Although a role in cardiovascular development can be expected, the hearts of Lrp2 knock out (ko) mice have not yet been investigated.Methods We studied the cardiovascular development of Lrp2 ko mice between embryonic day E10.5 and E15.5, applying morphometry and immunohistochemistry, using antibodies against Tfap2α (neural crest cells), Nkx2.5 (second heart field), WT1 (epicardium derived cells), tropomyosin (myocardium) and LRP2.Results The Lrp2 ko mice display a range of severe cardiovascular abnormalities including aortic arch anomalies, common arterial trunk with coronary anomalies, ventricular septal defects, overriding tricuspid valve and marked thinning of the ventricular myocardium. Both the neural crest cells and second heart field, which are essential for the lengthening and growth of the right ventricular outflow tract, are abnormally positioned in the Lrp2 ko. This explains the absence of the aorto-pulmonary septum leading to common arterial trunk and ventricular septal defects. Severe blebbing of the epicardial cells covering the ventricles is seen. Epithelial-mesenchymal transition does occur, however, there are less WT1 positive epicardium derived cells in the ventricular wall as compared to normal coinciding with the myocardial thinning and deep intertrabecular spaces.Conclusions LRP2 plays a crucial role in cardiovascular development in mice. This corroborates findings of cardiac anomalies in humans with LRP2 mutations. Future studies should reveal the underlying signaling mechanisms in which LRP2 is involved during cardiogenesis.
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    ABSTRACT: Background: Patients with chromosome 22q11.2 deletion syndrome (22q11DS) are at a seven fold increased risk of developing seizures. However, only a fraction of these patients exhibit structural abnormalities such as polymicrogyria (PMG) and periventricular nodular heterotopia (PNH) that are known to cause seizures and to be associated with 22q11DS. In this study we used a dedicated seizure imaging protocol to look for additional structural abnormalities in these individuals that may explain the elevated risk of seizure disorder in this patient group. Methods: Nineteen consecutive adult subjects with 22q11DS underwent a 3 Tesla MRI with a dedicated high-resolution seizure protocol. Neurological exam was performed in all patients. Genome-wide analysis excluded the presence of other pathogenic microdeletions or duplications. Results: Structural abnormalities were found in 11 of 14 subjects with sufficient image quality. These included three patients with PNH, one of whom had associated PMG. In addition, there was a surprisingly high prevalence of unilateral hippocampal malrotation (HIMAL), observed in 9 of 14 cases (64%). EEG findings showed interictal epileptiform discharges with focal distribution in four patients and generalized discharges in one patient. Conclusion: The results suggest that, in addition to other known structural abnormalities, 22q11DS is associated with HIMAL. It has been suggested that this developmental abnormality of the hippocampus may predispose or otherwise contribute to epileptogenesis. However in this study we observed HIMAL in a large proportion of patients, with and without epilepsy. Therefore, other as yet unknown factors may contribute to the high prevalence of epilepsy in this population.
    Full-text · Article · Sep 2013 · The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques
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    Full-text · Dataset · Sep 2013
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