Cancers are believed to arise from cancer stem cells (CSCs), but it is not known if these cells remain dependent upon the niche microenvironments that regulate normal stem cells. We show that endothelial cells interact closely with self-renewing brain tumor cells and secrete factors that maintain these cells in a stem cell-like state. Increasing the number of endothelial cells or blood vessels in orthotopic brain tumor xenografts expanded the fraction of self-renewing cells and accelerated the initiation and growth of tumors. Conversely, depletion of blood vessels from xenografts ablated self-renewing cells from tumors and arrested tumor growth. We propose that brain CSCs are maintained within vascular niches that are important targets for therapeutic approaches.
Cancer stem cells (CSC) are remarkably similar to normal stem cells: both self-renew, are multipotent and express common surface markers, e.g., PROMININ-1 (PROM1, CD133)1. What remains unclear is whether CSC are the direct progeny of mutated stem cells, or more mature cells that reacquire stem cell properties during tumor formation. Answering this important question will require knowledge of whether normal stem cells are susceptible to cancer causing mutations; however, this has proved difficult to test since the identity of most adult tissue stem cells is not known. Here, using an inducible-Cre-nuclear(n)LacZ reporter allele knocked into the Prom1 locus (Prom1C-L), we show that Prom1 is expressed in a variety of developing and adult tissues. Lineage-tracing studies of adult Prom1+/C-L mice containing the Rosa26YFP reporter allele showed that Prom1+ cells are located at the base of crypts in the small intestine, co-express Lgr52, generate the entire intestinal epithelium, and are therefore likely to be the small intestinal stem cell. Prom1 was reported recently to mark CSC of human intestinal tumors that arise frequently as a consequence of aberrant Wingless (WNT) signaling3-5. Activation of endogenous Wnt signaling in Prom1+/C-L mice containing a Cre-dependent mutant allele of Beta-catenin (Ctnnb1lox(ex3)) resulted first in a gross disruption of crypt architecture and a disproportionate expansion of Prom1+ cells at the crypt base. Lineage-tracing demonstrated that the progeny of these cells replaced the mucosa of the entire small intestine with neoplastic tissue that was characterized by focal high-grade intraepithelial neoplasia and crypt adenoma formation. Although all neoplastic cells arose from Prom1+ cells in these mice, only 7% of tumor cells retained Prom1 expression. Our data indicate that Prom1 marks stem cells in the adult small intestine, which are susceptible to transformation into tumors retaining a fraction of mutant-Prom1+ tumor cells.
During neurogenesis, the progression from a progenitor cell to a differentiated neuron is believed to be unidirectional and irreversible. The Rb family of proteins (Rb, p107, and p130) regulates cell-cycle exit and differentiation during retinogenesis. Rb and p130 are redundantly expressed in the neurons of the inner nuclear layer (INL) of the retina. We have found that in the adult Rb;p130-deficient retinae p107 compensation prevents ectopic proliferation of INL neurons. However, p107 is haploinsufficient in this process. Differentiated Rb(-/-);p107(+/-);p130(-/-) horizontal interneurons re-entered the cell cycle, clonally expanded, and formed metastatic retinoblastoma. Horizontal cells were not affected in Rb(+/-);p107(-/-);p130(-/-) or Rb(-/-);p107(-/-);p130(+/-), retinae suggesting that one copy of Rb or p130 was sufficient to prevent horizontal proliferation. We hereby report that differentiated neurons can proliferate and form cancer while maintaining their differentiated state including neurites and synaptic connections.
The phosphatidylinositol 3-kinase (PI3K) signaling pathway modulates growth, proliferation and cell survival in diverse tissue types and plays specialized roles in the nervous system including influences on neuronal polarity, dendritic branching and synaptic plasticity. The tumor-suppressor phosphatase with tensin homology (PTEN) is the central negative regulator of the PI3K pathway. Germline PTEN mutations result in cancer predisposition, macrocephaly and benign hamartomas in many tissues, including Lhermitte-Duclos disease, a cerebellar growth disorder. Neurological abnormalities including autism, seizures and ataxia have been observed in association with inherited PTEN mutation with variable penetrance. It remains unclear how loss of PTEN activity contributes to neurological dysfunction. To explore the effects of Pten deficiency on neuronal structure and function, we analyzed several ultra-structural features of Pten-deficient neurons in Pten conditional knockout mice. Using Golgi stain to visualize full neuronal morphology, we observed that increased size of nuclei and somata in Pten-deficient neurons was accompanied by enlarged caliber of neuronal projections and increased dendritic spine density. Electron microscopic evaluation revealed enlarged abnormal synaptic structures in the cerebral cortex and cerebellum. Severe myelination defects included thickening and unraveling of the myelin sheath surrounding hypertrophic axons in the corpus callosum. Defects in myelination of axons of normal caliber were observed in the cerebellum, suggesting intrinsic abnormalities in Pten-deficient oligodendrocytes. We did not observe these abnormalities in wild-type or conditional Pten heterozygous mice. Moreover, conditional deletion of Pten drastically weakened synaptic transmission and synaptic plasticity at excitatory synapses between CA3 and CA1 pyramidal neurons in the hippocampus. These data suggest that Pten is involved in mechanisms that control development of neuronal and synaptic structures and subsequently synaptic function. KeywordsPTEN; PI3K; brain; neurons; myelin; hypertrophy; synaptic plasticityThe tumor suppressor PTEN (phosphatase and tensin homolog, deleted on chromosome 10) is important in the modulation of cell growth, proliferation and survival. Inactivating mutations in both alleles of PTEN occur in diverse tumor types including glioblastoma multiforme (Chow and Baker, 2006). Consistent with the two-hit hypothesis of tumor suppression, inherited mutations in PTEN are associated with cancer predisposition, and the second allele of PTEN *To whom correspondence should be addressed: Suzanne.Baker@stjude.org; Phone: (901) 495-2254; FAX: (901) 495-2270. Section Editor: John L.R. Rubenstein, Developmental Neuroscience Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof bef...
Long-term potentiation (LTP) mediates learning and memory in the mammalian hippocampus. Whether a presynaptic or postsynaptic neuron principally enhances synaptic transmission during LTP remains controversial. Acute hippocampal slices were made from transgenic mouse strains that express synaptopHluorin in neurons. SynaptopHluorin is an indicator of synaptic vesicle recycling; thus, we monitored functional changes in presynaptic boutons of CA3 pyramidal cells by measuring changes in synaptopHluorin fluorescence. Simultaneously, we recorded field excitatory postsynaptic potentials to monitor changes in the strength of excitatory synapses between CA3 and CA1 pyramidal neurons. We found that LTP consists of two components, a slow presynaptic component and a fast postsynaptic component. The presynaptic mechanisms contribute mostly to the late phase of compound LTP, whereas the postsynaptic mechanisms are crucial during the early phase of LTP. We also found that protein kinase A (PKA) and L-type voltage-gated calcium channels are crucial for the expression of the presynaptic component of compound LTP, and NMDA channels are essential for that of the postsynaptic component of LTP. These data are the first direct evidence that presynaptic and postsynaptic components of LTP are temporally and mechanistically distinct.
Auditory hallucinations in schizophrenia are alleviated by antipsychotic agents that inhibit D2 dopamine receptors (Drd2s). The defective neural circuits and mechanisms of their sensitivity to antipsychotics are unknown. We identified a specific disruption of synaptic transmission at thalamocortical projections in the auditory cortex in murine models of schizophrenia-associated 22q11 deletion syndrome (22q11DS). This deficit is caused by an aberrant elevation of Drd2 in the thalamus, which renders 22q11DS thalamocortical projections sensitive to antipsychotics and causes a deficient acoustic startle response similar to that observed in schizophrenic patients. Haploinsufficiency of the microRNA-processing gene Dgcr8 is responsible for the Drd2 elevation and hypersensitivity of auditory thalamocortical projections to antipsychotics. This suggests that Dgcr8-microRNA-Drd2–dependent thalamocortical disruption is a pathogenic event underlying schizophrenia-associated psychosis.
The 22q11 deletion syndrome (22q11DS) is characterized by cognitive decline and increased risk of psychiatric disorders, mainly schizophrenia. The molecular mechanisms of neuronal dysfunction in cognitive symptoms of 22q11DS are poorly understood. Here, we report that a mouse model of 22q11DS, the Df(16)1/؉ mouse, exhibits substantially enhanced short-and long-term synaptic plasticity at hippocampal CA3-CA1 synapses, which coincides with deficits in hippocampus-dependent spatial memory. These changes are evident in mature but not young animals. Electrophysiological, two-photon imaging and glutamate uncaging, and electron microscopic assays in acute brain slices showed that enhanced neurotransmitter release but not altered postsynaptic function or structure caused these changes. Enhanced neurotransmitter release in Df(16)1/؉ mice coincided with altered calcium kinetics in CA3 presynaptic terminals and upregulated sarco(endo)plasmic reticulum calcium-ATPase type 2 (SERCA2). SERCA inhibitors rescued synaptic phenotypes of Df(16)1/؉ mice. Thus, presynaptic SERCA2 upregulation may be a pathogenic event contributing to the cognitive symptoms of 22q11DS.
Thalamocortical (TC) projections provide the major pathway for ascending sensory information to the mammalian neocortex. Arrays of these projections form synaptic inputs on thalamorecipient neurons, thus contributing to the formation of receptive fields (RFs) in sensory cortices. Experience-dependent plasticity of RFs persists throughout an organism’s lifespan, but in adults requires activation of cholinergic inputs to the cortex. In contrast, synaptic plasticity at TC projections is limited to the early postnatal period. This disconnect led to the widespread belief that TC synapses are the principle site of RF plasticity only in neonatal sensory cortices, but that they lose this plasticity upon maturation. Here we tested an alternative hypothesis that mature TC projections do not lose synaptic plasticity but rather acquire gating mechanisms that prevent the induction of synaptic plasticity. Using whole-cell recordings and direct measures of postsynaptic and presynaptic activity (two-photon glutamate uncaging and two-photon imaging of the FM 1–43 assay, respectively) at individual synapses in acute mouse brain slices that contain the auditory thalamus and cortex, we determined that long-term depression (LTD) persists at mature TC synapses but is gated presynaptically. Cholinergic activation releases presynaptic gating through M1 muscarinic receptors that downregulate adenosine inhibition of neurotransmitter release acting through A1 adenosine receptors. Once presynaptic gating is released, mature TC synapses can express LTD postsynaptically through group I metabotropic glutamate receptors. These results indicate that synaptic plasticity at TC synapses is preserved throughout the lifespan and, therefore, may be a cellular substrate of RF plasticity in both neonate and mature animals.
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