Chronic up‐regulation of sonic hedgehog has little effect on postnatal craniofacial morphology of euploid and trisomic mice. Issue 2 (6th December 2015)

• Record Type: Journal Article
• Authors: Singh, Nandini; Dutka, Tara; Reeves, Roger H.; Richtsmeier, Joan T.
• Is Part Of: Developmental dynamics. Volume 245:Issue 2(2016)
• Page Start: 114
• Page End: 122
• Publication Date: 2015-12-06
• Subjects: patched -- Down syndrome -- development -- Ts65Dn -- geometric morphometrics; Morphogenesis -- Periodicals; Anatomy -- Periodicals; Anatomie -- Périodiques; Biologie du développement -- Périodiques; 571.833
• DOI: 10.1002/dvdy.24361
• Languages: English
• ISSNs: 1058-8388

Abstract

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. Developmental Dynamics 245:114–122, 2016 . © 2015 Wiley Periodicals, Inc. Key Findings: sca overexpression mainly affects R3/R4 cell specification. ca interacts with genes encoding components of Notch signaling and proteins involved in intracellular transport. sca overexpression antagonizes Notch signaling in the Drosophila eye. Trafficking of Sca vesicles may depend on dynein function.