During development of the neocortex, the marginal zone (layer I) and the subplate (layer VII) are the first layers to form from a primordial plexiform neoropil. The cortical plate (layers II–VI) is subsequently established between these superficial and deep components of the primordial plexiform neuropil. Neurons in the early zones are thought to play important roles in the formation of the cortex: the Cajal-Retzius cells of the marginal zone are instrumental in neuronal migration and laminar formation, and cells of the subplate are involved in the formation of cortical connections. Using the fluorescent tracer 1,1′-dioctodecyl-3,3,3′,3′-tetramethylindocarbocyanine (DiI), we have shown here that a substantial proportion of neurons of the marginal zone, including cells with features of Cajal-Retzius cells, and of the subplate and lower intermediate zone are not born in the ventricular neuroepithelium but instead originate in the medial ganglionic eminence (MGE), the pallidal primordium. These neurons follow a tangential migratory route to their positions in the developing cortex. They express the neurotransmitter GABA but seem to lack the calcium binding protein calretinin; some migrating cells found in the marginal zone express reelin. In addition, migrating cells express the LIM-homeobox gene Lhx6, a characteristic marker of the MGE. It is suggested that this gene uniquely or in combination with other transcription factors may be involved in the decision of MGE cells to differentiate in situ or migrate to the neocortex.

Schwann cells (SCs) are among the most attractive cellular candidates for the development of remyelination therapies for CNS lesions. Yet, their integration in the CNS is inhibited by astrocytes and therefore the use of genetically modified SCs with improved properties is an alternative promising approach. Our strategy for ameliorating the therapeutic potential of SCs has been to alter their adhesive properties by expressing on their surface the polysialylated (PSA) form of the neural cell adhesion molecule NCAM. In the present study, SCs from transgenic GFP-mice were transduced with a retroviral vector encoding sialyl-transferase X (STX), the enzyme responsible for transferring PSA on NCAM. Engineered STX-GFP-SCs with sustained PSA expression were thus generated and were found to have improved ability to associate with astrocytes in vitro. Importantly, when these cells were transplanted in vivo in a mouse model of spinal cord injury they promoted faster and significantly greater functional recovery as compared to using SCs transduced with a control retroviral vector or no cells at all. Morphological analysis indicated that the improved locomotor recovery correlated with earlier and enhanced remyelination by grafted STX-GFP-SCs, increased remyelination by host SCs as well as enhanced differentiation/remyelination by resident oligodendrocyte precursors. Moreover, sprouting of regenerating serotonergic nerve fibres, which are known to be important for locomotion and recovery after injury, was observed into and across the lesion site. These results underline the potential therapeutic benefit of early activation of myelin-forming cells to differentiate and remyelinate severed axons thus restoring functions in CNS trauma and/or demyelinating diseases.

The monoamines serotonin (5-HT), noradrenaline (NA), and dopamine (DA), which are present in the developing brain apparently before they assume their neurotransmitter functions, are regarded as strong candidates for a role in the maturation of the cerebral cortex. Here we sought to investigate their effects on the generation and differentiation of cortical cell types. Slice cultures, prepared from the cortices of embryonic day (E) 14, E16, and E19 rat fetuses, were kept in defined medium or in defined medium plus 5-HT for 7 d. E16 cortices were also exposed to NA or DA for the same period. At the end of this period, the proportions of the neuronal [glutamate (Glu)-, GABA-, calbindin-, calretinin-labeled], glial (GFAP), and neuroepithelial (nestin) cell types were estimated for all conditions. We found that in E16 cultures, application of 5-HT, but not of NA or DA, significantly increased the proportion of Glu-containing neurons without affecting the overall neuronal population or the proportions of any other cell types. A similar effect was observed in co-cultures of E16 cortex with slices through the midbrain raphe nuclei of E19 rats. The total amount of cortical Glu, as measured with HPLC, was also increased in these co-cultures. To investigate whether the effect of 5-HT was the result of changes in cell proliferation, we exposed slices to bromodeoxyuridine (BrdU) and found that the proportion of BrdU-labeled cells was similar in the 5-HT-treated and control slices. These results indicate that 5-HT promotes the differentiation of cortical Glu-containing neurons without affecting neuroepithelial cell proliferation.

Mutations in the Parkin gene (PARK2) have been linked to a recessive form of Parkinson’s disease (PD) characterized by the loss of dopaminergic neurons in the substantia nigra. Deficiencies of mitochondrial respiratory chain complex I activity have been observed in the substantia nigra of PD patients, and loss of Parkin results in the reduction of complex I activity shown in various cell and animal models. Using co-immunoprecipitation and proximity ligation assays on endogenous proteins, we demonstrate that Parkin interacts with mitochondrial Stomatin-like protein 2 (SLP-2), which also binds the mitochondrial lipid cardiolipin and functions in the assembly of respiratory chain proteins. SH-SY5Y cells with a stable knockdown of Parkin or SLP-2, as well as induced pluripotent stem cell-derived neurons from Parkin mutation carriers, showed decreased complex I activity and altered mitochondrial network morphology. Importantly, induced expression of SLP-2 corrected for these mitochondrial alterations caused by reduced Parkin function in these cells. In-vivo Drosophila studies showed a genetic interaction of Parkin and SLP-2, and further, tissue-specific or global overexpression of SLP-2 transgenes rescued parkin mutant phenotypes, in particular loss of dopaminergic neurons, mitochondrial network structure, reduced ATP production, and flight and motor dysfunction. The physical and genetic interaction between Parkin and SLP-2 and the compensatory potential of SLP-2 suggest a functional epistatic relationship to Parkin and a protective role of SLP-2 in neurons. This finding places further emphasis on the significance of Parkin for the maintenance of mitochondrial function in neurons and provides a novel target for therapeutic strategies.

Demyelination occurs in several central nervous system (CNS) disorders, including multiple sclerosis, viral infection and spinal cord injury and can result in severe functional impairment. Therefore there is great interest in developing therapies promoting repair in CNS demyelinating diseases and trauma. Cell replacement therapy is an attractive approach for myelin repair, and experimental transplantation has provided convincing evidence of the repair potential of grafted myelin-forming cells. Schwann cells (SCs), oligodendrocyte progenitors, olfactory ensheathing cells and embryonic and neural stem cells have been shown to form myelin after transplantation into the demyelinated CNS. SCs are among the most promising candidates for autologous grafting. They can remyelinate spinal cord lesions after experimental demyelination, leading in some cases to functional recovery in rodent and primate models. However, SCs do not normally enter the CNS, and migration of SCs transplanted in CNS white matter is inhibited by astrocytes. As SC migration and myelination is mediated by interactions of sets of extracellular matrix molecules with cell surface molecules, genetic engineering of SCs to alter aspects of these interactions is a possible way forward. Thus efforts towards the development of SC-based therapies are focused in enhancing their migration and functional integration into the lesioned CNS. In addition, efforts are being made to use these cells as gene delivery vehicles for an array of molecules with repair potential. In this review we summarize data from the recent literature regarding the use of SCs in CNS repair and discuss the prospects for future therapeutic applications