Chronic up-regulation of sonic hedgehog has little effect on postnatal craniofacial morphology of euploid and trisomic mice.
BACKGROUND
In Ts65Dn, a mouse model of Down syndrome (DS), brain and craniofacial abnormalities that parallel those in people with DS are linked to an attenuated cellular response to sonic hedgehog (SHH) signaling. If a similarly reduced response to SHH occurs in all trisomic cells, then chronic up-regulation of the pathway might have a positive effect on development in trisomic mice, resulting in amelioration of the craniofacial anomalies.


RESULTS
We crossed Ts65Dn with Ptch1(tm1Mps/+) mice and quantified the craniofacial morphology of Ts65Dn;Ptch(+/-) offspring to assess whether a chronic up-regulation of the SHH pathway rescued DS-related anomalies. Ts65Dn;Ptch1(+/-) mice experience a chronic increase in SHH in SHH-receptive cells due to haploinsufficiency of the pathway suppressor, Ptch1. Chronic up-regulation had minimal effect on craniofacial shape and did not correct facial abnormalities in Ts65Dn;Ptch(+/-) mice. We further compared effects of this chronic up-regulation of SHH with acute pathway stimulation in mice treated on the day of birth with a SHH pathway agonist, SAG. We found that SHH affects facial morphology differently based on chronic vs. acute postnatal pathway up-regulation.


CONCLUSIONS
Our findings have implications for understanding the function of SHH in craniofacial development and for the potential use of SHH-based agonists to treat DS-related abnormalities.
Department of Anthropology, Pennsylvania State University, University Park, Pennsylvania.
Nandini
N
Singh
Institute of Genetic Medicine and Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Tara
T
Dutka
Institute of Genetic Medicine and Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Roger H
RH
Reeves
Department of Anthropology, Pennsylvania State University, University Park, Pennsylvania.
Joan T
JT
Richtsmeier
D000818:Animals; D019465:Craniofacial Abnormalities / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics* / Q000378:metabolism; D057895:Haploinsufficiency; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D015854:Up-Regulation
D053823:Hedgehog Proteins
Down syndrome; Ts65Dn; development; geometric morphometrics; patched