The association of cortical dysplasia and anterior horn arthrogryposis: a case report

We describe a 21-year-old woman with neurogenic congenital contractures (arthrogryposis) of the lower limbs, normal intelligence, hyper-reflexia and partial epilepsy. MRI revealed bilateral opercular (perisylvian) cortical dysplasia with infolding of cerebral cortex, a focal neuroblast migrational disorder. This type of migrational disorder is known to have a prenatal onset after the 20th fetal week, whereas the anterior horn cell degeneration responsible of neurogenic arthrogryposis originates at 12–14 weeks of gestation. A prenatal viral infection along the neural axis during both these gestational periods or a genetic defect could be responsible for both lesions in this case.     

Do oculomotor neuroblasts migrate across the midline in the fetal rat brain?

Summary Toluidine blue-stained semithin sections and Cajal-Castro preparations are used to study in rat fetuses whether oculomotor neuroblasts migrate across the midline at a certain period of development. In confirmation of previous studies, a group of oculomotor neuroblasts was detected which first grow cytoplasmic processes into the mesencephalic midline, and afterwards translocate their somata towards the midline, between the 12th and the 15th days of gestation. At this moment a midline mass of neuroblasts characterizes the meeting at this landmark of both left and right migrating neuroblastic groups. No crossing oculomotor axons yet are demonstrable with reduced silver techniques.In further stages of development the neuroblasts continue their migration until they arrive at the contralateral nucleus at the 16th and 17th day of gestation. At the midline the mass of neuroblasts disappears gradually and crossed oculomotor axons become visible.The electron microscope was then used to study ultrastructurally the migrating motoneurons. It was discovered that no preexisting structure guides their movement by contact. Their leading processes show no filopodial activity, and contain abundant microtubules and thick bundles of neurofilaments in eccentric position. The neuroblasts carry their axon across the midline as a trailing process.     

Chronic treatment of exendin-4 affects cell proliferation and neuroblast differentiation in the adult mouse hippocampal dentate gyrus

Exendin-4 isolated from Heloderma suspectum venom acts via glucagon-like peptide 1 (GLP-1) receptor and has clinically been used in the type 2 diabetes. In this study, we investigated the effects of exendin-4 on cell proliferation and neuroblast differentiation in the subgranular zone (SGZ) of the dentate gyrus in mice. Exendin-4 was treated intraperitoneally to male ICR mice twice a day for 21 days. The exendin-4-treated group showed a significantly higher number of Ki67- (1.51-fold), doublecortin (DCX)- (2.5-fold) and 5-bromo-2′-deoxyuridine (BrdU) + DCX- (2.46-fold) immunoreactive cells in the SGZ of the dentate gyrus compared to the control group. The results of this study showed that treatment with exendin-4 increased cell proliferation neuroblast differentiation in the SGZ of the dentate gyrus, suggesting that exendin-4 promotes structural plasticity in the dentate gyrus.     

Protein Phosphatase 4 mediates localization of the Miranda complex during Drosophila neuroblast asymmetric divisions

Asymmetric localization of cell fate determinants is a crucial step in neuroblast asymmetric divisions. Whereas several protein kinases have been shown to mediate this process, no protein phosphatase has so far been implicated. In a clonal screen of larval neuroblasts we identified the evolutionarily conserved Protein Phosphatase 4 (PP4) regulatory subunit PP4R3/Falafel (Flfl) as a key mediator specific for the localization of Miranda (Mira) and associated cell fate determinants during both interphase and mitosis. Flfl is predominantly nuclear during interphase/prophase and cytoplasmic after nuclear envelope breakdown. Analyses of nuclear excluded as well as membrane targeted versions of the protein suggest that the asymmetric cortical localization of Mira and its associated proteins during mitosis depends on cytoplasmic/membrane-associated Flfl, whereas nuclear Flfl is required to exclude the cell fate determinant Prospero (Pros), and consequently Mira, from the nucleus during interphase/prophase. Attenuating the function of either the catalytic subunit of PP4 (PP4C; Pp4-19C in Drosophila) or of another regulatory subunit, PP4R2 (PPP4R2r in Drosophila), leads to similar defects in the localization of Mira and associated proteins. Flfl is capable of directly interacting with Mira, and genetic analyses indicate that flfl acts in parallel to or downstream from the tumor suppressor lethal (2) giant larvae (lgl). Our findings suggest that Flfl may target PP4 to the MIra protein complex to facilitate dephosphorylation step(s) crucial for its cortical association/asymmetric localization.     

Effects of ADHD therapeutic agents,methylphenidate and atomoxetine,on hippocampal neurogenesis in the adolescent mouse dentate gyrus

Methylphenidate (MPH) and atomoxetine (ATX) are commonly used as attention-deficit/hyperactivity disorder (ADHD) therapeutic agents. In the present study, we investigated the effects of MPH and ATX on cell proliferation and neuronal differentiation in the dentate gyrus (DG) of the adolescent mouse by 5-bromo-2′-deoxyuridine (BrdU) and doublecortin (DCX) immunohistochemistry. BrdU-positive (⁺) cells, DCX⁺ cells and BrdU⁺/NeuN⁺ neurons (BrdU⁺ cells with NeuN immunoreaction) were easily detected in the subgranular zone (SGZ) of the DG in the vehicle-, MPH- and ATX-treated groups. Among them, only in the 10 mg/kg MPH-treated group, the numbers of BrdU⁺, DCX⁺ and BrdU⁺/NeuN⁺ cells were significantly increased compared to those in the vehicle-treated group. In addition, brain-derived neurotrophic factor (BDNF) level was significantly increased in 10 mg/kg MPH-treated group, not in the other experimental groups, compared to the vehicle-treated group. These results indicate that MPH, not ATX, can enhance cell proliferation and neuroblast differentiation in the SGZ of the DG via increasing BDNF level.     

Activation of neuroblast proliferation in explant culture of the Drosophila larval CNS

The developmental control of neuroblast proliferation is absolutely required for the assembly and function of the central nervous system. A lethal mutation in trol results in the failure of quiescent neuroblasts to begin division at the appropriate time. I have established a culture system in which quiescent neuroblasts in explants of Drosophila larval CNSs initiate cell division in vitro to normal in vivo levels. This activation requires removal of the CNS for culture after a specific developmental stage and the presence of fetal calf serum or a larval extract in the medium. Either supplement is effective when heat-treated. Substitution of the steroid hormone ecdysone or the non-steroidal ecdysone analog RH5992 for either fetal calf serum or larval extract also results in activation of neuroblast proliferation. Culture of trol^sd CNSs with wildtype larval extract or ecdysone results in the defective neuroblast proliferation phenotype observed in trol mutants in vivo, while culture of wildtype CNSs with trol^sd extract produces normal neuroblast proliferation.     

Porcine placental peptides improve neuroblast proliferation and differentiation via enhancement of TrkB and BDNF levels in D-glatacose-induced mouse aging model

Aging affects the nervous system as well as other organs.In our study, we aimed to study the pharmacological effects and mechanism of porcine placental peptides (PPP) in aging process, and to observe the changes of neuroblast proliferation and differentiation as well as partial gene expression in hippocampus of D-galactose-induced aged mouse. Based on the analysis of experimental results, it was confirmed that PPP significantly improved neurobalst proliferation and differentiation in the mouse hippocampal DG by ki-67 and DCX immunohistochemistry. This result showed that PPP had anti-aging effects on D-galactose-induced aging mouse model. Moreover, we observed up-regulated expressions of BDNF and TrkB proteins and down-regulated expressions of Caspase 3, 8, and 9 proteins in the PPP-treated mouse hippocampus. Therefore, our results showed that PPP obviouslyimproved neuroblast proliferation and differentiation, and its anti-aging effect might berelated to down-regulation of apoptosis-related proteins, including Caspase 3, 8, and 9, via BDNF/TrkB pathway. Our findings provided valuable evidence for its applications in the health and medicine sectors.     

Nanofibrous scaffolds releasing a small molecule BDNF-mimetic for the re-direction of endogenous neuroblast migration in the brain

Brain tissue engineering has the potential to harness existing elements of neurogenesis within the adult brain to overcome a microenvironment that is otherwise inhibitory to regeneration, especially following severe tissue damage. This study investigates the ability of electrospun poly ε-caprolactone (PCL) to re-direct the migratory pathway of endogenous neuroblasts from the disrupted subventricular zone (SVZ). A small molecule non-peptide ligand (BDNF-mimetic) that mimicked the trophic properties of brain-derived neurotrophic factor (BDNF) was incorporated into electrospun PCL scaffolds to improve neuroblast survival and promote neuroblast migration towards the implant. PCL scaffolds were able to support neuroblast infiltration and migration along the implant tract. In the presence of the BDNF-mimetic, neuroblasts were able to migrate towards the implant via the parenchyma, and their persistence within the implants was prolonged. In addition, the BDNF-mimetic improved implant integration and increased local neuronal plasticity by increasing neurite sprouting at the tissue-implant interface. SMI32+ neurites were observed inside scaffolds at 21 days but not 8 days post implantation, indicating that at least some of the infiltrated neuroblasts had differentiated into neurons.     

Regenerative Medicine in Historical Context

The phrase “regenerative medicine” is used so often and for so many different things, with such enthusiasm or worry, and often with a sense that this is something radically new. This paper places studies of regeneration and applications in regenerative medicine into historical perspective. In fact, the first stem cell experiment was carried out in 1907, and many important lines of research have contributed since. This paper explores both what we can learn about the history and what we can learn from the history of regenerative medicine research.

Differential effects of cyclin-dependent kinase blockers upon cell death in the developing retina

Pharmacological blockers of cyclin-dependent kinases (CDKs) can inhibit cell cycle progression. Deferoxamine (DFO) and mimosine (MIMO) arrest cells reversibly at the G1/S transition and olomoucine (OLO) inhibits the cell cycle at both G1/S and G2/M. We investigated the effect of these drugs upon cell death in histotypical explants taken from the retina of neonatal rats. Degeneration of retinal ganglions cells (RGC) induced by axotomy was inhibited by OLO (100 microM) but not by DFO (up to 2 mM) or MIMO (up to 1 mM). On the other hand, after 1 day in vitro, all cell cycle inhibitors induced cell death in the neuroblastic layer (NBL) of the explants. DFO and MIMO induced cell death only of proliferating cells, identified either by their incorporation of bromodeoxyuridine or by immunolabeling the proliferating cell nuclear antigen. In turn, OLO induced cell death of both proliferating and post-mitotic cells. However, the post-mitotic cells were unlabeled with markers of retinal differentiation. Our results indicate that cyclin-dependent kinases are involved in the control of sensitivity to cell death in the retina, and that retinal cells present differentiation-dependent responses to modulation of CDK activity.