No abstract

J. Neurochem. (2012) 120, 964–973. Abstract During pregnancy, activation of the maternal immune system results in inflammation in the foetal nervous system. The causative agents are pro‐inflammatory cytokines like interleukin‐1β (IL‐1β), produced by the foetus. In this study, we examine the effect of IL‐1β on the proliferation and differentiation of neural progenitor cells (NPCs) to better understand its potential effects on the developing brain. We find that the IL‐1β receptor (IL‐1R1) is expressed in the ventral mesencephalon of the developing brain. Furthermore, IL‐1R1 is expressed on Nestin‐positive, Sox‐2‐positive NPCs. IL‐1β treatment reduced the numbers of proliferating NPCs, an effect prevented by the IL‐1R1 receptor antagonist. LDH and MTT assays, and western blot analysis for cleaved caspase 3 and poly(ADP‐ribose) polymerase, confirmed that this was not due to an increase in cell death but rather an induction of differentiation. To further study the effects of IL‐1β on cell fate determination, we differentiated NPCs in the presence and absence of IL‐1β. Il‐1β promoted gliogenesis and inhibited neurogenesis, an effect that required p38‐MAPK kinase signalling. In summary, these data show that exposure of NPCs to IL‐1β affects their development. This necessitates an examination of the consequences that maternal immune system activation during pregnancy has on the cellular architecture of the developing brain.

Ventral midbrain (VM) dopaminergic (DA) neurons project to the dorsal striatum via the nigrostriatal pathway to regulate voluntary movements, and their loss leads to the motor dysfunction seen in Parkinson's disease (PD). Despite recent progress in the understanding of VM DA neurogenesis, the factors regulating nigrostriatal pathway development remain largely unknown. The bone morphogenetic protein (BMP) family regulates neurite growth in the developing nervous system and may contribute to nigrostriatal pathway development. Two related members of this family, BMP2 and growth differentiation factor (GDF)5, have neurotrophic effects, including promotion of neurite growth, on cultured VM DA neurons. However, the molecular mechanisms regulating their effects on DA neurons are unknown. By characterising the temporal expression profiles of endogenous BMP receptors (BMPRs) in the developing and adult rat VM and striatum, this study identified BMP2 and GDF5 as potential regulators of nigrostriatal pathway development. Furthermore, through the use of noggin, dorsomorphin and BMPR/Smad plasmids, this study demonstrated that GDF5-and BMP2-induced neurite outgrowth from cultured VM DA neurons is dependent on BMP type I receptor activation of the Smad 1/5/8 signalling pathway.

[1] Two-dimensional inversions of lithospheric-probing magnetotelluric (MT) data at a total of 20 sites acquired along an approximately east-west 300-km-long profile across the Wopmay orogen in the Northwest Territories, Canada, provide electrical resistivity models of the boundary between the Archean Slave craton and the adjacent Proterozoic Bear Province. An analysis of distortion effects and structural dimensionality indicates that the MT responses are primarily one-dimensional or only weakly two-dimensional with a depth-independent geoelectric strike angle of N32°E, consistent with regional structural geology. The regional-scale model, generated from the longer period responses from all of the sites along the profile, reveals significant lateral variations in the lithospheric mantle. Resistive cratonic roots are imaged to depths of $200 km beneath both the Slave craton and the Hottah terrane of the Bear Province. These are separated by a less resistive region beneath the Great Bear magmatic zone, which is speculatively interpreted as a consequence of a decrease in the grain size of olivine in the Wopmay mantle, caused by localized shearing, compared to its neighboring cratonic roots. Focused two-dimensional models, from higher frequency responses at sites on specific sections of the profile, reveal the resistivity structure at crustal depths beneath the region. These suggest that the root of the Slave craton crosses beneath the Wopmay orogen, and that the Wopmay fault zone does not penetrate into the lower crust. A comparison of these results with those obtained during the Lithoprobe project farther south shows striking along strike variations in the conductivity structure associated with the Wopmay orogen.

A greater understanding of the mechanisms that promote the survival and growth of dopaminergic neurons is essential for the advancement of cell replacement therapies for Parkinson's disease (PD). Evidence supports a role for the mitogen-activated protein kinase p38 in the demise of dopaminergic neurons, while mitogen-activated protein kinase phosphatase-1 (MKP-1), which negatively regulates p38 activity, has not yet been investigated in this context. Here, we show that MKP-1 is expressed in dopaminergic neurons cultured from E14 rat ventral mesencephalon (VM). When dopaminergic neurons were transfected to overexpress MKP-1, they displayed a more complex morphology than their control counterparts in vitro. Specifically, MKP-1-transfection induced significant increases in neurite length and branching with a maximum increase observed in primary branches. We demonstrate that inhibition of dopaminergic neurite growth induced by treatment of rat VM neurons with the dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA) in vitro is mediated by p38 and is concomitant with a significant and selective decrease in MKP-1 expression in these neurons. We further show that overexpression of MKP-1 in dopaminergic neurons contributes to neuroprotection against the effects of 6-OHDA. Collectively, we report that MKP-1 can promote the growth and elaboration of dopaminergic neuronal processes and can help protect them from the neurotoxic effects of 6-OHDA. Thus, we propose that strategies aimed at augmenting MKP-1 expression or activity may be beneficial in protecting dopaminergic neurons and may provide potential therapeutic approaches for PD.