DiGeorge Syndrome Phenotypes Reflect Disrupted Interaction Between Inductive Signals and 22q11 Genes

Gopalakrishna, Deepak

DiGeorge Syndrome Phenotypes Reflect Disrupted Interaction Between Inductive Signals and 22q11 Genes Public Deposited

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March 22, 2019

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Gopalakrishna, Deepak
- Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology

Abstract

We asked whether similar phenotypes that result from diminished 22q11 gene dosage and altered Sonic Hedgehog (Shh), Fibroblast Growth Factor (Fgf), Retinoic Acid (RA) or Bone morphogenetic protein (Bmp) signaling reflect interactions between 22q11 genes and these cardinal morphogenetic signals. When Shh, RA, Fgf, or Bmp signaling is disrupted, expression levels, but not patterns, of several 22q11 genes change in mid-gestation mouse embryos, with most substantial changes associated with altered Shh signaling. When 22q11 gene expression is diminished in mouse embryos by a deletion similar to that in DiGeorge/22q11 Deletion Syndrome (22q11DS), expression of a subset of Shh-, RA-, and Bmp-, but not Fgf-related signaling molecules is altered, with several RA intermediates most substantially changed. Shh and RA signaling, quantified using reporter mice, is altered in the brain or heart of 22q11 deleted, but not Tbx1+/-embryos, even though diminished Tbx1 dosage has been suggested as essential for 22q11DS phenotypes. Brief pharmacological disruption of Shh signaling in mid-gestation 22q11-deleted or wild type, embryos leads to severe dysmorphology. Disrupted RA signaling introduces or enhances brain and heart phenotypes in 22q11-deleted but not wild type or Tbx1+/- embryos. Thus, early heart and brain morphogenesis depends on interactions between Shh and RA signaling and 22q11 gene dosage. Apparently, 22q11 gene dosage sustains normal morphogenesis by maintaining a dynamic range of signaling that, when altered, may intensify cardiovascular and CNS phenotypes in 22q11DS.

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