TY - JOUR
T1 - 22q11 Gene dosage establishes an adaptive range for sonic hedgehog and retinoic acid signaling during early development
AU - Maynard, Thomas M.
AU - Gopalakrishna, Deepak
AU - Meechan, Daniel W.
AU - Paronett, Elizabeth M.
AU - Newbern, Jason M.
AU - LaMantia, Anthony Samuel
N1 - Funding Information:
This work was supported by an American Heart Association (grant 0815067E to D.G.), National Institutes of Health (grants NICHD042182 and NIMH64065 to A.-S.L.) as well as NINDS NS031768 to the University of North Carolina Neuroscience Center Expression Profiling and In Situ Hybridization core facilities, and S10RR025565 from the National Center for Research Resources for GWU Center for Microscopy Imaging and Analysis.
PY - 2013/1
Y1 - 2013/1
N2 - We asked whether key morphogenetic signaling pathways interact with 22q11 gene dosage to modulate the severity of cranial or cardiac anomalies in DiGeorge/22q1 deletion 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, an Shh inhibitor, or carrying mutations in Gli3Xtj, an Shh-signaling effector, have morphogenetic anomalies that are either not seen, or seen at significantly lower frequenciesin 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.
AB - We asked whether key morphogenetic signaling pathways interact with 22q11 gene dosage to modulate the severity of cranial or cardiac anomalies in DiGeorge/22q1 deletion 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, an Shh inhibitor, or carrying mutations in Gli3Xtj, an Shh-signaling effector, have morphogenetic anomalies that are either not seen, or seen at significantly lower frequenciesin 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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U2 - 10.1093/hmg/dds429
DO - 10.1093/hmg/dds429
M3 - Article
C2 - 23077214
AN - SCOPUS:84871546292
SN - 0964-6906
VL - 22
SP - 300
EP - 312
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 2
M1 - dds429
ER -