title: 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.
authors.affiliation: Department of Human and General Physiology, University of Bologna, Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Contestabile
authors.forename: Tatiana
authors.initials: T
authors.lastname: Fila
authors.forename: Claudio
authors.initials: C
authors.lastname: Ceccarelli
authors.forename: Paola
authors.initials: P
authors.lastname: Bonasoni
authors.forename: Laura
authors.initials: L
authors.lastname: Bonapace
authors.forename: Donatella
authors.initials: D
authors.lastname: Santini
authors.forename: Renata
authors.initials: R
authors.lastname: Bartesaghi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ciani
mesh_terms: D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics*; D049109:Cell Proliferation; D002891:Chromosomes, Human, Pair 21; D019925:Cyclin A / Q000378:metabolism; D018891:Dentate Gyrus / Q000196:embryology / Q000473:pathology*; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics / Q000473:pathology*; D005260:Female; D005333:Fetus; D006657:Histones / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019579:Neocortex / Q000196:embryology / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000473:pathology; D014314:Trisomy
chemical_list: D019925:Cyclin A; D006657:Histones; D019394:Ki-67 Antigen; D009419:Nerve Tissue Proteins; D001973:Bromodeoxyuridine