Nandini Singh1, Tara Dutka2, Roger H Reeves2, Joan T Richtsmeier1. 1. Department of Anthropology, Pennsylvania State University, University Park, Pennsylvania. 2. Institute of Genetic Medicine and Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Abstract
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.
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.
Authors: Laura G Reinholdt; Yueming Ding; Griffith J Gilbert; Griffith T Gilbert; Anne Czechanski; Jeffrey P Solzak; Randall J Roper; Mark T Johnson; Leah Rae Donahue; Cathleen Lutz; Muriel T Davisson Journal: Mamm Genome Date: 2011-09-28 Impact factor: 2.957
Authors: Nathan M Young; Diane Hu; Alexis J Lainoff; Francis J Smith; Raul Diaz; Abigail S Tucker; Paul A Trainor; Richard A Schneider; Benedikt Hallgrímsson; Ralph S Marcucio Journal: Development Date: 2014-03 Impact factor: 6.868
Authors: Eric W Fish; Scott E Parnell; Kathleen K Sulik; Lorinda K Baker; Laura B Murdaugh; David Lamson; Kevin P Williams Journal: Birth Defects Res Date: 2017-01-20 Impact factor: 2.344
Authors: Lauren Welby; Hailey Caudill; Gelila Yitsege; Ali Hamad; Filiz Bunyak; Irene E Zohn; Thomas Maynard; Anthony-Samuel LaMantia; David Mendelowitz; Teresa E Lever Journal: Front Neurol Date: 2020-01-31 Impact factor: 4.003