Cell cycle alteration and decreased cell proliferation in the hippocampal dentate gyrus and in the neocortical germinal matrix of fetuses with down syndrome and in Ts65Dn mice

Abstract

Down syndrome (DS), the leading genetic cause of mental retardation, is characterized by reduced number of cortical neurons and brain size. The occurrence of these defects starting from early life stages points at altered developmental neurogenesis as their major determinant. The goal of our study was to obtain comparative evidence for impaired neurogenesis in the hippocampal dentate gyrus (DG) of DS fetuses and Ts65Dn mice, an animal model for DS. Cell proliferation in human fetuses was evaluated with Ki-67 (a marker of cells in S + G(2) + M phases of cell cycle) and cyclin A (a marker of cells in S phase) immunohistochemistry. We found that in the DG of DS fetuses the number of proliferating cells was notably reduced when compared with controls. A similar reduction was observed in the germinal matrix of the lateral ventricle. In both structures, DS fetuses showed a reduced ratio between cyclin A- and Ki-67-positive cells when compared with controls, indicating that they had a reduced number of cycling cells in S phase. In the DG of P2 Ts65Dn mice cell proliferation, assessed 2 h after an injection of bromodeoxyuridine (BrdU), was notably reduced, similarly to DS fetuses. After 28 days, Ts65Dn mice had still less BrdU-positive cells than controls. Phenotypic analysis of the surviving cells showed that Ts65Dn mice had a percent number of cells with astrocytic phenotype larger than controls. Using phospho-histone H3 immunohistochemistry we found that both DS fetuses and P2 Ts65Dn mice had a higher number of proliferating cells in G(2) and a smaller number of cells in M phase of cell cycle. Results provide novel evidence for proliferation impairment in the hippocampal DG of the DS fetal brain, comparable to that of the P2 mouse model, and suggest that cell cycle alterations may be critical determinants of the reduced proliferation potency.

The Amyloid Precursor Protein (APP) Triplicated Gene Impairs Neuronal Precursor Differentiation and Neurite Development through Two Different Domains in the Ts65Dn Mouse Model for Down Syndrome

“…Consistently with this idea, recent evidence has shown a severe impairment of cellular proliferation in the ventricular germinal matrix and various structures of the hippocampal region and cerebellum of human fetuses with DS (5)(6)(7). This proliferation impairment is worsened by impaired cell fate specification with a reduction in neuronogenesis and an increase in astrogliogenesis (5)(6)(7). This evidence suggests that proliferation impairment and cell fate specification may be key determinants of intellectual disability in individuals with DS.…”

“…The hypocellularity observed in the primary visual cortex, primary somatosensory cortex, primary motor cortex, primary auditory cortex, and superior temporal gyrus of individuals with DS led to the hypothesis that proliferation deficits may underlie the typical hypocellularity of the DS brain (3,4). Consistently with this idea, recent evidence has shown a severe impairment of cellular proliferation in the ventricular germinal matrix and various structures of the hippocampal region and cerebellum of human fetuses with DS (5)(6)(7). This proliferation impairment is worsened by impaired cell fate specification with a reduction in neuronogenesis and an increase in astrogliogenesis (5)(6)(7).…”

Altered neurogenesis in mouse models of Alzheimer disease

“…41 DS is caused by a triplication of chromosome 21, which involves an elevation of the APP gene dose. Ts65Dn mice contain 3 copies of most of the genes of murine chromosome 16 that are homologues for human chromosome 21 genes.…”

Dyrk1A Phosphorylates p53 and Inhibits Proliferation of Embryonic Neuronal Cells

“…The brains of DS patients exhibit an arrest of neurogenesis in many CNS regions, including the hippocampus at all ages, even the fetal stage (4 -6). Cell proliferation has been shown to be impaired in human fetal DS brains and Ts65Dn mouse brains (7,8). Ts65Dn mouse possesses an extra copy of a part of chromosome 16, which corresponds to human chromosome 21, and also shows learning and memory impairments and altered neuronal proliferation in the hippocampus (8 -10).…”