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.
We previously obtained evidence for reduced cell proliferation in the dentate gyrus (DG) of fetuses with Down syndrome (DS), suggesting that the hippocampal hypoplasia seen in adulthood may be caused by defective early neuron production. The goal of this study was to establish whether DS fetuses (17-21 weeks of gestation) exhibit reduction in total cell number in the DG, hippocampus and parahippocampal gyrus (PHG). Volumes of the cellular layers and cell number were estimated with Cavalieri's principle and the optical fractionator method, respectively. We found that in DS fetuses all investigated structures had a reduced volume and cell number. Analysis of cell phenotype showed that DS fetuses had a higher percentage of cells with astrocytic phenotype but a smaller percentage of cells with neuronal phenotype. Immunohistochemistry for Ki-67, a marker of cycling cells, showed that DS fetuses had less proliferating cells in the germinal zones of the hippocampus and PHG. We additionally found that in the hippocampal region of DS fetuses there was a higher incidence of apoptotic cell death. Results show reduced neuron number in the DS hippocampal region and suggest that this defect is caused by disruption of neurogenesis and apoptosis, two fundamental processes underlying brain building.
Mutations in cyclin-dependent kinase-like 5 (CDKL5) cause early-onset epileptic encephalopathy, a neurodevelopmental disorder with similarities to Rett Syndrome. Here we describe the physiological, molecular, and behavioral phenotyping of a Cdkl5 conditional knockout mouse model of CDKL5 disorder. Behavioral analysis of constitutive Cdkl5 knockout mice revealed key features of the human disorder, including limb clasping, hypoactivity, and abnormal eye tracking. Anatomical, physiological, and molecular analysis of the knockout uncovered potential pathological substrates of the disorder, including reduced dendritic arborization of cortical neurons, abnormal electroencephalograph (EEG) responses to convulsant treatment, decreased visual evoked responses (VEPs), and alterations in the Akt/rpS6 signaling pathway. Selective knockout of Cdkl5 in excitatory and inhibitory forebrain neurons allowed us to map the behavioral features of the disorder to separable cell-types. These findings identify physiological and molecular deficits in specific forebrain neuron populations as possible pathological substrates in CDKL5 disorder.
Down syndrome (DS) is a genetic pathology characterized by intellectual disability and brain hypotrophy. Widespread neurogenesis impairment characterizes the fetal and neonatal DS brain, strongly suggesting that this defect may be a major determinant of mental retardation. Our goal was to establish, in a mouse model for DS, whether early pharmacotherapy improves neurogenesis and cognitive behavior. Neonate Ts65Dn mice were treated from postnatal day (P) 3 to P15 with fluoxetine, an antidepressant that inhibits serotonin (5-HT) reuptake and increases proliferation in the adult Ts65Dn mouse (Clark et al., 2006). On P15, they received a BrdU injection and were killed after either 2 h or 1 month. Results showed that P15 Ts65Dn mice had notably defective proliferation in the hippocampal dentate gyrus, subventricular zone, striatum, and neocortex and that proliferation was completely rescued by fluoxetine. In the hippocampus of untreated P15 Ts65Dn mice, we found normal 5-HT levels but a lower expression of 5-HT1A receptors and brain-derived neurotrophic factor (BDNF). In Ts65Dn mice, fluoxetine treatment restored the expression of 5-HT1A receptors and BDNF. One month after cessation of treatment, there were more surviving cells in the dentate gyrus of Ts65Dn mice, more cells with a neuronal phenotype, more proliferating precursors, and more granule cells. These animals were tested for contextual fear conditioning, a hippocampusdependent memory task, and exhibited a complete recovery of memory performance. Results show that early pharmacotherapy with a drug usable by humans can correct neurogenesis and behavioral impairment in a model for DS.
We previously reported the identification of mZac, a novel mouse zinc finger protein that shared with p53 the ability to regulate concomitantly apoptosis and cell cycle progression. We describe here the isolation, chromosomal localization, and functional in vitro characterization of its human homolog. hZAC is a widely expressed zinc finger protein that reveals transactivation and DNA-binding activity. hZAC inhibits tumor cell growth through induction of apoptotic cell death and G 1 arrest. Thus hZAC, like its mouse counterpart, displays antiproliferative properties through pathways known to be central to the activity of p53. We mapped hZAC on chromosome 6q24-q25, a region frequently deleted in many solid tumors. Indeed, allelic loss at 6q24-q25 has been shown in breast and ovary cancers, melanomas, astrocytomas, and renal cell carcinomas. Furthermore, Abdollahi et al.
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