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Publications (53)
Throughout adulthood neural stem cells divide in neurogenic niches–the dentate gyrus of the hippocampus and the subventricular zone–producing progenitor cells and new neurons. Stem cells self-renew, thus preserving their pool. Furthermore, the number of stem/progenitor cells in the neurogenic niches decreases with age. We have previously demonstrat...
Aging is a multi-faceted process caused by the accumulation of cellular damage over time, associated with a gradual reduction of physiological activities in cells and organs. This degeneration results in a reduced ability to adapt to homeostasis perturbations and an increased incidence of illnesses such as cognitive decline, neurodegenerative and c...
Neuron generation persists throughout life in the hippocampus but is altered in animal models of neurological and neuropsychiatric diseases, suggesting that disease-associated decline in cognitive and emotional hippocampal-dependent behaviours might be functionally linked with dysregulation of post-natal neurogenesis. Depletion of the adult neural...
The dentate gyrus of the hippocampus and the subventricular zone are neurogenic niches where neural stem and progenitor cells replicate throughout life to generate new neurons. The Btg1 gene maintains the stem cells of the neurogenic niches in quiescence. The deletion of Btg1 leads to an early transient increase of stem/progenitor cells division, f...
We have previously generated a mouse model (Ptch1+/−/Tis21KO ), which displays high frequency spontaneous medulloblastoma, a pediatric tumor of the cerebellum. Early postnatal cerebellar granule cell precursors (GCPs) of this model show, in consequence of the deletion of Tis21, a defect of the Cxcl3-dependent migration. We asked whether this migrat...
In the adult mammalian brain new neurons are continuously generated throughout life in two niches, the dentate gyrus of the hippocampus and the subventricular zone. This process, called adult neurogenesis, starts from stem cells, which are activated and enter the cell cycle. The proliferative capability of stem cells progressively decreases during...
About 30% of medulloblastomas (MBs), a tumor of the cerebellum, arise from cerebellar granule cell precursors (GCPs) undergoing transformation following activation of the Sonic hedgehog (Shh) pathway. To study this process, we generated a new MB model by crossing Patched1 heterozygous (Ptch1+/−) mice, which develop spontaneous Shh-type MBs, with mi...
The dentate gyrus of the hippocampus is one of two brain areas generating throughout life new neurons, which contribute to the formation of episodic/associative memories. During aging, the production of new neurons decreases and a cognitive decline occurs. Dietary factors influence neuronal function and synaptic plasticity; among them the phenolic...
In the neurogenic niches—the dentate gyrus of the hippocampus and the subventricular zone (SVZ) adjacent to lateral ventricles—stem cells continue to divide during adulthood, generating progenitor cells and new neurons, and to self-renew, thus maintaining the stem cell pool. During aging, the numbers of stem/progenitor cells in the neurogenic niche...
p16Ink4a mRNA expression increases with age in the dentate gyrus. Real-time PCR analysis was performed on RNA obtained from the dentate gyrus of 2- and 12-month-old p16Ink4a wild-type and knockout mice. Three mice per group were analyzed. Average ± SEM values were obtained by analyzing the dentate gyrus of each of the three mice with three technica...
Two-way ANOVA analyses of experiments (main effects are analyzed by Fisher F test followed by analysis of simple effects with PLSD test).
Representative images by confocal microscopy of dividing type-1–2a (Ki67+/nestin+/DCX−), type-2b (Ki67+/nestin+/DCX+) and type-3 cells (Ki67+/nestin−/DCX+) in the p16Ink4a wild-type and knockout dentate gyrus of sedentary and exercised mice. Ki67+, nestin+, DCX+ cells are in green, red, and blue, respectively. Nuclei are identified by Hoechst 33258...
Levene’s test analysis of normality of variances, followed by non-parametric analysis of main factor effects with Kruskal-Wallis test and simple effect analysis with Mann-Whitney U test.
Of wide interest for health is the relation existing between depression, a very common psychological illness, accompanied by anxiety and reduced ability to concentrate, and adult neurogenesis.
We will focus on two neurogenic stimuli, fluoxetine and physical exercise, both endowed with the ability to activate adult neurogenesis in the dentate gyrus...
Medulloblastoma (MB), the tumor of the cerebellum, is the most frequent brain cancer in childhood and a major cause of pediatric mortality. Based on gene profiling, four MB subgroups have been identified, i.e., Wnt or Sonic Hedgehog (Shh) types, and subgroup 3 or 4. The Shh-type MB has been shown to arise from the cerebellar precursors of granule n...
AAV efficiently infects MB nodule cells.
Representative confocal images of sections from nodules infected with AAV-GFP or AAV-CBA viruses and stained for the nuclei dye Hoechst (blue). Green fluorescence indicates GFP-positive cells. Scale bars: 50 μm.
(TIF)
AAV-Tis21 infects MB nodule cells and expresses exogenous Tis21.
Representative sections (4x magnification) of two nodules infected with AAV-CBA (A, A’) and two nodules infected with AAV-Tis21 (B, B’), showing the expression of Tis21 mRNA labeled by in situ hybridization. Tis21 mRNA expression is higher in AAV-Tis21 infected nodules (see enlargemen...
Supplemental materials and methods.
In situ Hybridization.
(DOCX)
Cell proliferation and differentiation are interdependent processes. Here, we have asked to what extent the two processes of neural progenitor cell amplification and differentiation are functionally separated. Thus, we analyzed whether it is possible to rescue a defect of terminal differentiation in progenitor cells of the dentate gyrus, where new...
Fluoxetine treatment induces after 7 days a significant increase of the number of dentate gyrus progenitor cells in adult wild-type mice, as detected following multiple BrdU injections. (A) Representative confocal images (40× magnification) showing proliferating dentate gyrus progenitor cells, labeled by BrdU (red), in mice treated as described in...
Morris water maze (MWM) escape latency in wild-type and mutant mice. The MWM was performed as in Farioli-Vecchioli et al. (2009) with minor modifications. In this task, mice learn across daily sessions to find a hidden escape platform using extra-maze visual cues. Tis21KO and Tis21WT mice (both groups, n = 5) performed equally in the task. Statisti...
Fluoxetine, administered with a protocol highlighting proliferation and differentiation, rescues stage 5 but not stage 6 neurons defective for terminal differentiation in Tis21 knockout mice. (A) Representative confocal images (40×) showing stage 5 (BrdU+/Calretinin+/NeuN+; white arrowheads), and stage 6 neurons, (BrdU+/Calretinin−/NeuN+), treated...
Medulloblastoma (MB), tumor of the cerebellum, remains a leading cause of cancer-related mortality in childhood. We previously showed, in a mouse model of spontaneous MB (Ptch1+/-/Tis21-/-), that a defect of the migration of cerebellar granule neuron precursor cells (GCPs) correlates with an increased frequency of MB. This occurs because GCPs, rath...
We have recently generated a novel medulloblastoma (MB) mouse model with activation of the Shh pathway and lacking the MB suppressor Tis21 (Patched1+/-/Tis21
KO
). Its main phenotype is a defect of migration of the cerebellar granule precursor cells (GCPs). By genomic analysis of GCPs in vivo, we identified as drug target and major responsible of t...
PC3/Tis21 is a transcriptional cofactor that inhibits proliferation in several cell types, including neural progenitors. Here we report that PC3/Tis21 associates with HDAC1, HDAC4 and HDAC9 in vivo, in fibroblast cells. Furthermore, when HDAC1, HDAC4 or HDAC9 are silenced in fibroblasts or in a line of cerebellar progenitor cells, the ability of PC...
Il medulloblastoma (MB), la più frequente neoplasia maligna dell’infanzia, è dovuto ad alterazioni molecolari della morfogenesi del cervelletto. Circa il 30% origina da precursori delle cellule dei granuli cerebellari (PGC) ed una delle vie di segnale responsabili, se deregolata, è la Sonic HedgeHog (Shh). I trattamenti attuali includono resezione...
Cerebellar granule neurons develop postnatally from cerebellar granule precursors (GCPs), which are located in the external granule layer (EGL) where they massively proliferate. Thereafter, GCPs become postmitotic, migrate inward to form the internal granule layer (IGL), further differentiate and form synapses with Purkinje cell dendrites. We previ...
The PC3/Tis21/Btg2 and Btg1 genes are transcriptional cofactors belonging to the Btg/Tob family, which regulate the development of several cell types, including neural precursors. We summarize here the actions of these genes on neural precursors in the adult neurogenic niches and the cognitive defects associated when their expression is altered. We...
Physical exercise increases the generation of new neurons in adult neurogenesis. However, only few studies have investigated the beneficial effects of physical exercise in paradigms of impaired neurogenesis. Here we demonstrate that running fully reverses the deficient adult neurogenesis within the hippocampus and subventricular zone of the lateral...
Bone morphogenic proteins (BMPs) and the Notch pathway regulate quiescence and self-renewal of stem cells of the subventricular zone (SVZ), an adult neurogenic niche. Here we analyze the role at the intersection of these pathways of Tis21 (Btg2/PC3), a gene regulating proliferation and differentiation of adult SVZ stem and progenitor cells. In Tis2...
Within the hippocampal circuitry, the basic function of the dentate gyrus is to transform the memory input coming from the enthorinal cortex into sparse and categorized outputs to CA3, in this way separating related memory information. New neurons generated in the dentate gyrus during adulthood appear to facilitate this process, allowing a better s...
A failure in the control of proliferation of cerebellar granule neuron precursor cells (GCPs), located in the external granular layer (EGL) of the cerebellum, gives rise to medulloblastoma. To investigate the process of neoplastic transformation of GCPs, we generated a new medulloblastoma model by crossing Patched1 heterozygous mice, which develop...
Btg1 belongs to a family of cell cycle inhibitory genes. We observed that Btg1 is highly expressed in adult neurogenic niches, i.e., the dentate gyrus and subventricular zone (SVZ). Thus, we generated Btg1 knockout mice to analyze the role of Btg1 in the process of generation of adult new neurons. Ablation of Btg1 causes a transient increase of the...
In skeletal muscle cells, the PC4 (Tis7/Ifrd1) protein is known to function as a coactivator of MyoD by promoting the transcriptional
activity of myocyte enhancer factor 2C (MEF2C). In this study, we show that up-regulation of PC4 in vivo in adult muscle significantly potentiates injury-induced regeneration by enhancing myogenesis. Conversely, we o...
Decrease of neurons expressing NeuroD1 in the dentate gyrus of PC3/Tis21-null mice. (A) In P60 PC3/Tis21-null mice the total number of NeuroD1-positive cells was significantly reduced, of about 15%. (B, C) Consistently, new neurons 1- to 5-day-old expressing NeuroD1, identified either as (B) BrdU/NeuroD1-positive, or as (C) BrdU/NeuroD1/NeuN-positi...
Analysis of type-2ab progenitor cells through the Tbr2 marker. An analysis in the dentate gyrus of P60 PC3/Tis21-null and PC3/Tis21+/+ mice of the number of proliferating progenitors cells, using the type-2 population marker Tbr2, showed (A) no change within the whole type-2ab population (Ki67/Tbr2-positive, p = 0.88) or (B) in type-2a progenitor c...
Laser capture microdissection of the dentate gyrus in P14 PC3/Tis21-null mice. (A-E) Representative images outlining the computer-assisted procedure of laser capture microdissection of the dentate gyrus, from cresyl violet-stained histological slides obtained from P14 PC3/Tis21-null or WT mice. (A, B) 4x magnification images of the whole hippocampu...
No differences between PC3/Tis21+/+ and PC3/Tis21−/− in basal behaviors and anxiety levels. (A-F) Basal behaviors and anxiety levels were evaluated in the open field and plus maze tests, respectively. (A-C) The open field test was carried out in a circular arena (60 cm of diameter) made in grey Plexiglas surrounded by walls (20 cm high). Animals we...
Neurogenesis in the dentate gyrus of the adult hippocampus has been implicated in neural plasticity and memory, but the molecular mechanisms controlling the proliferation and differentiation of newborn neurons and their integration into the synaptic circuitry are still largely unknown. To investigate this issue, we have analyzed the adult hippocamp...
Adult neurogenesis in the dentate gyrus plays a critical role in hippocampus-dependent spatial learning. It remains unknown, however, how new neurons become functionally integrated into spatial circuits and contribute to hippocampus-mediated forms of learning and memory. To investigate these issues, we used a mouse model in which the differentiatio...
PC3 Transgene Activation Does Not Affect Nonlearning Aspects in the Morris Water Maze
(A) TgPC3 ON (n = 10), TgPC3 OFF (n = 8) and WT (n = 23) mice showed no significant differences in the amount of time spent near walls (thigmotaxis) across learning (trial/block 1–18; F(2,38) = 3.19; p = not significant) and reversal learning (trial/block 19–30; F...
Impaired Learning in the Morris Water Maze Is Not Related to Indirect Effects of PC3 Over-Expression
(A) Experimental timeline as a function of mouse age in days. To rule out the possibility of indirect effects of PC3 over-expression in nestin-positive cells on neighboring, mature granule cells, TgPC3 ON (n = 9) mice and their controls (WT, n = 8)...
Lack of Integration of New Neurons into Dentate Gyrus Memory Circuits Correlates with Impairment of Spatial Learning in the Morris Water Maze
(A) Escape latency during training (left panel) and time spent in quadrants during the probe test (right panel) of TgPC3 ON (n = 6) and WT (n = 6) mice analyzed for c-fos expression 4 wk after BrdU administra...
Medulloblastoma, the most common brain tumor in childhood, appears to originate from cerebellar granule cell precursors (GCPs), located in the external granular layer (EGL) of the cerebellum. The antiproliferative gene PC3 (Tis21/BTG2) promotes cerebellar neurogenesis by inducing GCPs to shift from proliferation to differentiation. To assess whethe...
Histone deacetylase 4 (HDAC4) negatively regulates skeletal myogenesis by associating with the myocyte enhancer factor 2 (MEF2) transcription factors. Our data indicate that the gene PC4 (interferon-related developmental regulator 1 [IFRD1], Tis7), which we have previously shown to be required for myoblast differentiation, is both induced by MyoD a...
We identified in the EST database murine and human sequences similar, but not identical, to the members of the PC3/BTG/TOB family of cell cycle inhibitors. A conserved domain (aa 50-68) of the PC3 protein, the prototype member of the family, was used as a query. That domain has been shown by us to be necessary for the antiproliferative activity of...
The p53-inducible gene PC3 (TIS21, BTG2) is endowed with antiproliferative activity. Here we report that expression ofPC3 in cycling cells induced accumulation of hypophosphorylated, growth-inhibitory forms of pRb and led to G1 arrest. This latter was not observed in cells with genetic disruption of the Rb gene, indicating that thePC3-mediated G1 a...
