Dual and opposing roles of primary cilia in medulloblastoma development.

Recent work has shown that primary cilia are essential for Hedgehog (Hh) signaling during mammalian development. It is also known that aberrant Hh signaling can lead to cancer, but the role of primary cilia in oncogenesis is not known. Cerebellar granule neuron precursors (GNPs) can give rise to medulloblastomas, the most common malignant brain tumor in children. The primary cilium and Hh signaling are required for GNP proliferation. We asked whether primary cilia in GNPs have a role in medulloblastoma growth in mice. Genetic ablation of primary cilia blocked medulloblastoma formation when this tumor was driven by a constitutively active Smoothened protein (Smo), an upstream activator of Hh signaling. In contrast, removal of cilia was required for medulloblastoma growth by a constitutively active glioma-associated oncogene family zinc finger-2 (GLI2), a downstream transcription factor. Thus, primary cilia are either required for or inhibit medulloblastoma formation, depending on the initiating oncogenic event. Remarkably, the presence or absence of cilia was associated with specific variants of human medulloblastomas; primary cilia were found in medulloblastomas with activation in HH or WNT signaling but not in most medulloblastomas in other distinct molecular subgroups. Primary cilia could serve as a diagnostic tool and provide new insights into the mechanism of tumorigenesis

Computational Models of Adult Neurogenesis

Experimental results in recent years have shown that adult neurogenesis is a significant phenomenon in the mammalian brain. Little is known, however, about the functional role played by the generation and destruction of neurons in the context of and adult brain. Here we propose two models where new projection neurons are incorporated. We show that in both models, using incorporation and removal of neurons as a computational tool, it is possible to achieve a higher computational efficiency that in purely static, synapse-learning driven networks. We also discuss the implication for understanding the role of adult neurogenesis in specific brain areas.Comment: To appear Physica A, 7 page

Cell cycle and lineage progression of neural progenitors in the ventricular-subventricular zones of adult mice

Proliferating neural stem cells and intermediate progenitors persist in the ventricular-subventricular zone (V-SVZ) of the adult mammalian brain. This extensive germinal layer in the walls of the lateral ventricles is the site of birth of different types of interneurons destined for the olfactory bulb. The cell cycle dynamics of stem cells (B1 cells), intermediate progenitors (C cells), and neuroblasts (A cells) in the V-SVZ and the number of times these cells divide remain unknown. Using whole mounts of the walls of the lateral ventricles of adult mice and three cell cycle analysis methods using thymidine analogs, we determined the proliferation dynamics of B1, C, and A cells in vivo. Achaete-scute complex homolog (Ascl)1(+) C cells were heterogeneous with a cell cycle length (T(C)) of 18–25 h and a long S phase length (T(S)) of 14–17 h. After C cells, Doublecortin(+) A cells were the second-most common dividing cell type in the V-SVZ and had a T(C) of 18 h and T(S) of 9 h. Human glial fibrillary acidic protein (hGFAP)::GFP(+) B1 cells had a surprisingly short Tc of 17–18 h and a T(S) of 4 h. Progenitor population analysis suggests that following the initial division of B1 cells, C cells divide three times and A cells once, possibly twice. These data provide essential information on the dynamics of adult progenitor cell proliferation in the V-SVZ and how large numbers of new neurons continue to be produced in the adult mammalian brain

"Antelope": a hybrid-logic model checker for branching-time Boolean GRN analysis

<p>Abstract</p> <p>Background</p> <p>In Thomas' formalism for modeling gene regulatory networks (GRNs), <it>branching time</it>, where a state can have <it>more than one possible future</it>, plays a prominent role. By representing a certain degree of unpredictability, branching time can model several important phenomena, such as (a) asynchrony, (b) incompletely specified behavior, and (c) interaction with the environment. Introducing more than one possible future for a state, however, creates a difficulty for ordinary simulators, because <it>infinitely many </it>paths may appear, limiting ordinary simulators to statistical conclusions. <it>Model checkers </it>for branching time, by contrast, are able to prove properties in the presence of infinitely many paths.</p> <p>Results</p> <p>We have developed <it>Antelope </it>("Analysis of Networks through TEmporal-LOgic sPEcifications", <url>http://turing.iimas.unam.mx:8080/AntelopeWEB/</url>), a model checker for analyzing and constructing Boolean GRNs. Currently, software systems for Boolean GRNs use branching time almost exclusively for asynchrony. <it>Antelope</it>, by contrast, also uses branching time for incompletely specified behavior and environment interaction. We show the usefulness of modeling these two phenomena in the development of a Boolean GRN of the <it>Arabidopsis thaliana </it>root stem cell niche.</p> <p>There are two obstacles to a direct approach when applying model checking to Boolean GRN analysis. First, ordinary model checkers normally only verify whether or not a <it>given </it>set of model states has a given property. In comparison, a model checker for Boolean GRNs is preferable if it <it>reports </it>the set of states having a desired property. Second, for efficiency, the expressiveness of many model checkers is limited, resulting in the inability to express some interesting properties of Boolean GRNs.</p> <p><it>Antelope </it>tries to overcome these two drawbacks: Apart from reporting the set of all states having a given property, our model checker can express, at the expense of efficiency, some properties that ordinary model checkers (e.g., NuSMV) cannot. This additional expressiveness is achieved by employing a logic extending the standard Computation-Tree Logic (CTL) with hybrid-logic operators.</p> <p>Conclusions</p> <p>We illustrate the advantages of <it>Antelope </it>when (a) modeling incomplete networks and environment interaction, (b) exhibiting the set of all states having a given property, and (c) representing Boolean GRN properties with hybrid CTL.</p

Origins and Proliferative States of Human Oligodendrocyte Precursor Cells.

Human cerebral cortex size and complexity has increased greatly during evolution. While increased progenitor diversity and enhanced proliferative potential play important roles in human neurogenesis and gray matter expansion, the mechanisms of human oligodendrogenesis and white matter expansion remain largely unknown. Here, we identify EGFR-expressing "Pre-OPCs" that originate from outer radial glial cells (oRGs) and undergo mitotic somal translocation (MST) during division. oRG-derived Pre-OPCs provide an additional source of human cortical oligodendrocyte precursor cells (OPCs) and define a lineage trajectory. We further show that human OPCs undergo consecutive symmetric divisions to exponentially increase the progenitor pool size. Additionally, we find that the OPC-enriched gene, PCDH15, mediates daughter cell repulsion and facilitates proliferation. These findings indicate properties of OPC derivation, proliferation, and dispersion important for human white matter expansion and myelination

Unique Organization of the Nuclear Envelope in the Post-natal Quiescent Neural Stem Cells

Neural stem cells (B1 astrocytes; NSCs) in the adult ventricular-subventricular-zone (V-SVZ) originate in the embryo. Surprisingly, recent work has shown that B1 cells remain largely quiescent. They are reactivated postnatally to function as primary progenitors for neurons destined for the olfactory bulb and some corpus callosum oligodendrocytes. The cellular and molecular properties of quiescent B1 cells remain unknown. Here we found that a subpopulation of B1 cells has a unique nuclear envelope invagination specialization similar to envelope-limited chromatin sheets (ELCS), reported in certain lymphocytes and some cancer cells. Using molecular markers, [3H]thymidine birth-dating, and Ara-C, we found that B1 cells with ELCS correspond to quiescent NSCs. ELCS begin forming in embryonic radial glia cells and represent a specific nuclear compartment containing particular epigenetic modifications and telomeres. These results reveal a unique nuclear compartment in quiescent NSCs, which is useful for identifying these primary progenitors and study their gene regulation