title: Chronic up-regulation of the SHH pathway normalizes some developmental effects of trisomy in Ts65Dn mice.
abstract: Down Syndrome (DS) is a highly complex developmental genetic disorder caused by trisomy for human chromosome 21 (Hsa21). All individuals with DS exhibit some degree of brain structural changes and cognitive impairment; mouse models such as Ts65Dn have been instrumental in understanding the underlying mechanisms. Several phenotypes of DS might arise from a reduced response of trisomic cells to the Sonic Hedgehog (SHH) growth factor. If all trisomic cells show a similar reduced response to SHH, then up-regulation of the pathway in trisomic cells might ameliorate multiple DS phenotypes. We crossed Ptch1tm1Mps/+ mice, in which the canonical SHH pathway is expected to be up-regulated in every SHH-responsive cell due to the loss of function of one allele of the pathway suppressor, Ptch1, to the Ts65Dn DS model and assessed the progeny for possible rescue of multiple DS-related phenotypes. Down-regulation of Ptch produced several previously unreported effects on development by itself, complicating interpretation of some phenotypes, and a number of structural or behavioral effects of trisomy were not compensated by SHH signaling. However, a deficit in a nest-building task was partially restored in Ts;Ptch+/- mice, as were the structural anomalies of the cerebellum seen in Ts65Dn mice. These results extend the body of evidence indicating that reduced response to SHH in trisomic cells and tissues contributes to various aspects of the trisomic phenotype.
authors.affiliation: Department of Physiology and Institute for Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Tara
authors.initials: T
authors.lastname: Dutka
authors.affiliation: Department of Physiology and Institute for Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Dorothy
authors.initials: D
authors.lastname: Hallberg
authors.affiliation: Department of Physiology and Institute for Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: rreeves@jhmi.edu.
authors.forename: Roger H
authors.initials: RH
authors.lastname: Reeves
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000473:pathology; D004314:Down Syndrome / Q000378:metabolism* / Q000503:physiopathology / Q000523:psychology; D005260:Female; D057895:Haploinsufficiency; D053823:Hedgehog Proteins / Q000378:metabolism*; D008297:Male; D018782:Maze Learning; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009425:Nesting Behavior; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D045442:Rotarod Performance Test; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D053823:Hedgehog Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; C465570:Shh protein, mouse
keywords: Behavior; Brain; Development; Down syndrome; Hedgehog