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1.
Cell Rep ; 20(5): 1148-1160, 2017 08 01.
Article in English | MEDLINE | ID: mdl-28768199

ABSTRACT

Cells initiate fate decisions during G1 phase by converting extracellular signals into distinctive cell cycle kinetics. The DNA replication timing is determined in G1 phase; lengthened G1 and hastened S phases correlate with increased neurogenic propensity of neural progenitor cells (NPCs), although the underlying molecular control remains elusive. Here, we report that proper G1 phase completion in NPCs requires Brap, a Ras-Erk signaling modulator with ubiquitin E3 ligase activity. We identified Skp2 and Skp2-associated SCF ubiquitin ligase as a key target of Brap-mediated polyubiquitination. Loss of Brap resulted in elevated Skp2, which increased p27Kip1 destruction, leading to G1 phase truncation and premature S phase entry. The aberrantly executed G1 in Brap-mutant NPCs, followed by hindered S phase progression and increased G2 phase arrest, which together prolonged the cell cycle, impeded neuronal differentiation and culminated in microcephaly. These findings demonstrate that neuronal differentiation is potentiated during G1 phase by Brap-directed cascade of events in cell signaling and protein turnover.


Subject(s)
Cell Differentiation , G1 Phase/physiology , Neural Stem Cells/metabolism , Neurons/metabolism , S Phase/physiology , Signal Transduction , Ubiquitin-Protein Ligases/metabolism , Animals , Cyclin-Dependent Kinase Inhibitor p27/genetics , Cyclin-Dependent Kinase Inhibitor p27/metabolism , G2 Phase Cell Cycle Checkpoints/genetics , Mice , Mice, Mutant Strains , Neural Stem Cells/cytology , S-Phase Kinase-Associated Proteins/genetics , S-Phase Kinase-Associated Proteins/metabolism , Ubiquitin-Protein Ligases/genetics
2.
Elife ; 52016 09 24.
Article in English | MEDLINE | ID: mdl-27664421

ABSTRACT

Neuronal fate-restricted intermediate progenitors (IPs) are derived from the multipotent radial glia (RGs) and serve as the direct precursors for cerebral cortical neurons, but factors that control their neurogenic plasticity remain elusive. Here we report that IPs' neuron production is enhanced by abrogating filamin function, leading to the generation of periventricular neurons independent of normal neocortical neurogenesis and neuronal migration. Loss of Flna in neural progenitor cells (NPCs) led RGs to undergo changes resembling epithelial-mesenchymal transition (EMT) along with exuberant angiogenesis that together changed the microenvironment and increased neurogenesis of IPs. We show that by collaborating with ß-arrestin, Flna maintains the homeostatic signaling between the vasculature and NPCs, and loss of this function results in escalated Vegfa and Igf2 signaling, which exacerbates both EMT and angiogenesis to further potentiate IPs' neurogenesis. These results suggest that the neurogenic potential of IPs may be boosted in vivo by manipulating Flna-mediated neurovascular communication.


Subject(s)
Filamins/metabolism , Neurogenesis , Neuroglia/physiology , Stem Cells/physiology , Up-Regulation , Animals , Filamins/deficiency , Mice , Mice, Knockout , Neovascularization, Physiologic
3.
Dev Cell ; 25(3): 241-55, 2013 May 13.
Article in English | MEDLINE | ID: mdl-23673330

ABSTRACT

Regulating cell proliferation and differentiation in CNS development requires both extraordinary complexity and precision. Neural progenitors receive graded overlapping signals from midline signaling centers, yet each makes a unique cell fate decision in a spatiotemporally restricted pattern. The Nde1-Lis1 complex regulates individualized cell fate decisions based on the geographical location with respect to the midline. While cells distant from the midline fail to self-renew in the Nde1-Lis1 double-mutant CNS, cells embedded in the signaling centers showed marked overproliferation. A direct interaction between Lis1 and Brap, a mitogen-activated protein kinase (MAPK) signaling threshold modulator, mediates this differential response to mitogenic signal gradients. Nde1-Lis1 deficiency resulted in a spatially dependent alteration of MAPK scaffold Ksr and hyperactivation of MAPK. Epistasis analyses supported synergistic Brap and Lis1 functions. These results suggest that a molecular complex composed of Nde1, Lis1, and Brap regulates the dynamic MAPK signaling threshold in a spatially dependent fashion.


Subject(s)
1-Alkyl-2-acetylglycerophosphocholine Esterase/metabolism , Cell Cycle Proteins/metabolism , MAP Kinase Signaling System , Microtubule-Associated Proteins/metabolism , Neocortex/metabolism , 1-Alkyl-2-acetylglycerophosphocholine Esterase/genetics , Animals , Cell Cycle Proteins/genetics , Cell Proliferation , Cells, Cultured , Embryo, Mammalian/metabolism , Embryo, Mammalian/pathology , Epistasis, Genetic , Immunohistochemistry , Mice , Mice, Inbred C57BL , Mice, Knockout , Microtubule-Associated Proteins/genetics , Multiprotein Complexes/metabolism , Mutation , Neocortex/enzymology , Neocortex/pathology , Neurogenesis , Neurons/enzymology , Neurons/metabolism , Neurons/pathology , Protein Interaction Mapping , Protein Kinases/genetics , Protein Kinases/metabolism , Protein Structure, Tertiary , Spinal Cord/metabolism , Spinal Cord/pathology
4.
J Amino Acids ; 2013: 240537, 2013.
Article in English | MEDLINE | ID: mdl-23606945

ABSTRACT

Because taurine alleviates ethanol- (EtOH-) induced lipid peroxidation and liver damage in rats, we asked whether exogenous taurine could alleviate EtOH-induced oxidative stress in chick embryos. Exogenous EtOH (1.5 mmol/Kg egg or 3 mmol/Kg egg), taurine (4 µmol/Kg egg), or EtOH and taurine (1.5 mmol EtOH and 4 µmol taurine/Kg egg or 3 mmol EtOH and 4 µmol taurine/Kg egg) were injected into fertile chicken eggs during the first three days of embryonic development (E0-2). At 11 days of development (midembryogenesis), serum taurine levels and brain caspase-3 activities, homocysteine (HoCys) levels, reduced glutathione (GSH) levels, membrane fatty acid composition, and lipid hydroperoxide (LPO) levels were measured. Early embryonic EtOH exposure caused increased brain apoptosis rates (caspase-3 activities); increased brain HoCys levels; increased oxidative-stress, as measured by decreased brain GSH levels; decreased brain long-chain polyunsaturated levels; and increased brain LPO levels. Although taurine is reported to be an antioxidant, exogenous taurine was embryopathic and caused increased apoptosis rates (caspase-3 activities); increased brain HoCys levels; increased oxidative-stress (decreased brain GSH levels); decreased brain long-chain polyunsaturated levels; and increased brain LPO levels. Combined EtOH and taurine treatments also caused increased apoptosis rates and oxidative stress.

5.
Biotechnol Biofuels ; 3: 2, 2010 Jan 15.
Article in English | MEDLINE | ID: mdl-20150993

ABSTRACT

BACKGROUND: Biofuels offer a viable alternative to petroleum-based fuel. However, current methods are not sufficient and the technology required in order to use lignocellulosic biomass as a fermentation substrate faces several challenges. One challenge is the need for a robust fermentative microorganism that can tolerate the inhibitors present during lignocellulosic fermentation. These inhibitors include the furan aldehyde, furfural, which is released as a byproduct of pentose dehydration during the weak acid pretreatment of lignocellulose. In order to survive in the presence of furfural, yeast cells need not only to reduce furfural to the less toxic furan methanol, but also to protect themselves and repair any damage caused by the furfural. Since furfural tolerance in yeast requires a functional pentose phosphate pathway (PPP), and the PPP is associated with reactive oxygen species (ROS) tolerance, we decided to investigate whether or not furfural induces ROS and its related cellular damage in yeast. RESULTS: We demonstrated that furfural induces the accumulation of ROS in Saccharomyces cerevisiae. In addition, furfural was shown to cause cellular damage that is consistent with ROS accumulation in cells which includes damage to mitochondria and vacuole membranes, the actin cytoskeleton and nuclear chromatin. The furfural-induced damage is less severe when yeast are grown in a furfural concentration (25 mM) that allows for eventual growth after an extended lag compared to a concentration of furfural (50 mM) that prevents growth. CONCLUSION: These data suggest that when yeast cells encounter the inhibitor furfural, they not only need to reduce furfural into furan methanol but also to protect themselves from the cellular effects of furfural and repair any damage caused. The reduced cellular damage seen at 25 mM furfural compared to 50 mM furfural may be linked to the observation that at 25 mM furfural yeast were able to exit the furfural-induced lag phase and resume growth. Understanding the cellular effects of furfural will help direct future strain development to engineer strains capable of tolerating or remediating ROS and the effects of ROS.

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