Chronic up-regulation of sonic hedgehog has little effect on postnatal craniofacial morphology of euploid and trisomic mice

Nandini Singh, Tara Dutka, Roger H Reeves, Joan T. Richtsmeier

Research output: Contribution to journalArticle

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 Ptch1tm1Mps/+ 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.

Original languageEnglish (US)
Pages (from-to)114-122
Number of pages9
JournalDevelopmental Dynamics
Volume245
Issue number2
DOIs
StatePublished - Feb 1 2016

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Hedgehogs
Up-Regulation
Down Syndrome
Craniofacial Abnormalities
Haploinsufficiency
Parturition

Keywords

  • Development
  • Down syndrome
  • Geometric morphometrics
  • Patched
  • Ts65Dn

ASJC Scopus subject areas

  • Developmental Biology

Cite this

Chronic up-regulation of sonic hedgehog has little effect on postnatal craniofacial morphology of euploid and trisomic mice. / Singh, Nandini; Dutka, Tara; Reeves, Roger H; Richtsmeier, Joan T.

In: Developmental Dynamics, Vol. 245, No. 2, 01.02.2016, p. 114-122.

Research output: Contribution to journalArticle

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