Defective cerebellar response to mitogenic Hedgehog signaling in Down's syndrome mice

Abstract

Trisomy 21 is the cause of Down's syndrome (DS) which is characterized by a number of phenotypes, including a brain which is small and hypocellular compared to that of euploid individuals. The cerebellum is disproportionately reduced. Ts65Dn mice are trisomic for orthologs of about half of the genes on human chromosome 21 and provide a genetic model for DS. These mice display a number of developmental anomalies analogous to those in DS, including a small cerebellum with a significantly decreased number of both granule and Purkinje cell neurons. Here we trace the origin of the granule cell deficit to precursors in early postnatal development, which show a substantially reduced mitogenic response to Hedgehog protein signaling. Purified cultures of trisomic granule cell precursors show a reduced but dose-dependent response to the Sonic hedgehog protein signal in vitro , demonstrating that this is a cell-autonomous deficit. Systemic treatment of newborn trisomic mice with a small molecule agonist of Hedgehog pathway activity increases mitosis and restores granule cell precursor populations in vivo . These results demonstrate a basis for and a potential therapeutic approach to a fundamental aspect of CNS pathology in DS.

Nurturing brain plasticity: impact of environmental enrichment

“…146,147 The most intensively studied mouse model of DS is the Ts65Dn line, 148 which summarizes the main hallmarks of the DS phenotype, including characteristic craniofacial abnormalities, impaired spatial and non-spatial learning abilities and attention deficits. [149][150][151][152][153][154] At the cellular level, Ts65Dn mice have a reduced number of hippocampal and cerebellar neurons, 155,156 impaired neurogenesis in the dentate gyrus of the hippocampus in both young and aged adults 157,158 and a prominent reduction in dendritic branching in several brain regions, accompanied by alterations in spine size and shape. 159 It is noteworthy that DS is also associated with reduced hippocampal neurogenesis 160 and volume 161 in humans.…”

Early-occurring proliferation defects in peripheral tissues of the Ts65Dn mouse model of Down syndrome are associated with patched1 over expression

“…Cerebellar granule cell precursors, 5 precursors from the neural crest 43 and from the SVZ 13 of trisomic mice exhibit a significant deficit in the Shh-induced mitogenic response. We have previously shown that this defect is related to an increased expression of Ptch1.…”

“…The DS brain is characteristically small, and accumulating evidence in human fetuses with DS and DS mouse models clearly shows that this defect is due to widespread neurogenesis impairment that can be traced back to very early developmental stages. [2][3][4][5][6][7] Consequently, neurogenesis defects leading to brain hypocellularity appear to be a major determinant of cognitive disability in DS.…”

Age-related changes in memory and in acetylcholine functions in the hippocampus in the Ts65Dn mouse, a model of Down syndrome

“…Also, as in humans with Down syndrome (cf. Shapiro, 2001), the volume of the cerebellum of Ts65Dn mice is reduced, with decreased numbers of both granule and Purkinje cells perhaps resulting from dysfunctions of cell signaling mechanisms during development (Olson et al, 2004;Roper et al, 2006). Thus, understanding of the neural and cognitive phenotypic differences between partial trisomy mice and diploid mice will require assessments of many variables across age.…”