Pyramidal neurons of the neocortex can be subdivided into two major groups: deep- (DL) and upper-layer (UL) neurons. Here we report that the expression of the AT-rich DNA-binding protein Satb2 defines two subclasses of UL neurons: UL1 (Satb2 positive) and UL2 (Satb2 negative). In the absence of Satb2, UL1 neurons lose their identity and activate DL- and UL2-specific genetic programs. UL1 neurons in Satb2 mutants fail to migrate to superficial layers and do not contribute to the corpus callosum but to the corticospinal tract, which is normally populated by DL axons. Ctip2, a gene required for the formation of the corticospinal tract, is ectopically expressed in all UL1 neurons in the absence of Satb2. Satb2 protein interacts with the Ctip2 genomic region and controls chromatin remodeling at this locus. Satb2 therefore is required for the initiation of the UL1-specific genetic program and for the inactivation of DL- and UL2-specific genes.
Age-associated decline in regeneration capacity limits the restoration of nervous system functionality after injury. In a model for demyelination, we found that old mice fail to resolve the inflammatory response initiated after myelin damage. Aged phagocytes accumulated excessive amounts of myelin debris, which triggered cholesterol crystal formation and phagolysosomal membrane rupture and stimulated inflammasomes. Myelin debris clearance required cholesterol transporters, including apolipoprotein E. Stimulation of reverse cholesterol transport was sufficient to restore the capacity of old mice to remyelinate lesioned tissue. Thus, cholesterol-rich myelin debris can overwhelm the efflux capacity of phagocytes, resulting in a phase transition of cholesterol into crystals and thereby inducing a maladaptive immune response that impedes tissue regeneration.
During CNS development, oligodendrocytes wrap their plasma membrane around axons to generate multilamellar myelin sheaths. To drive growth at the leading edge of myelin at the interface with the axon, mechanical forces are necessary, but the underlying mechanisms are not known. Using an interdisciplinary approach that combines morphological, genetic, and biophysical analyses, we identified a key role for actin filament network turnover in myelin growth. At the onset of myelin biogenesis, F-actin is redistributed to the leading edge, where its polymerization-based forces push out non-adhesive and motile protrusions. F-actin disassembly converts protrusions into sheets by reducing surface tension and in turn inducing membrane spreading and adhesion. We identified the actin depolymerizing factor ADF/cofilin1, which mediates high F-actin turnover rates, as an essential factor in this process. We propose that F-actin turnover is the driving force in myelin wrapping by regulating repetitive cycles of leading edge protrusion and spreading.
Recombinant human erythropoietin (EPO) improves cognitive performance in
neuropsychiatric diseases ranging from schizophrenia and multiple sclerosis to
major depression and bipolar disease. This consistent EPO effect on cognition is
independent of its role in hematopoiesis. The cellular mechanisms of action in
brain, however, have remained unclear. Here we studied healthy young mice and
observed that 3-week EPO administration was associated with an increased number
of pyramidal neurons and oligodendrocytes in the hippocampus of ~20%.
Under constant cognitive challenge, neuron numbers remained elevated until >6
months of age. Surprisingly, this increase occurred in absence of altered cell
proliferation or apoptosis. After feeding a 15N-leucine diet, we used
nanoscopic secondary ion mass spectrometry, and found that in EPO-treated mice,
an equivalent number of neurons was defined by elevated 15N-leucine
incorporation. In EPO-treated NG2-Cre-ERT2 mice, we confirmed enhanced
differentiation of preexisting oligodendrocyte precursors in the absence of
elevated DNA synthesis. A corresponding analysis of the neuronal lineage awaits
the identification of suitable neuronal markers. In cultured neurospheres, EPO
reduced Sox9 and stimulated miR124, associated with advanced neuronal
differentiation. We are discussing a resulting working model in which EPO drives
the differentiation of non-dividing precursors in both (NG2+)
oligodendroglial and neuronal lineages. As endogenous EPO expression is induced
by brain injury, such a mechanism of adult neurogenesis may be relevant for
central nervous system regeneration.
Summary
Nedd4-1 is a ‘Neuronal Precursor Cell Expressed and Developmentally Downregulated Protein’ and among the most abundant E3 ubiquitin ligases in mammalian neurons. In analyses of conventional and conditional Nedd4-1 deficient mice, we found that Nedd4-1 plays a critical role in dendrite formation. Nedd4-1, the serine/threonine kinase TNIK, and Rap2A form a complex that controls Nedd4-1-mediated ubiquitination of Rap2A. Ubiquitination by Nedd4-1 inhibits Rap2A function, which reduces the activity of Rap2 effector kinases of the TNIK family and promotes dendrite growth. We conclude that a Nedd4-1/Rap2A/TNIK signaling pathway regulates neurite growth and arborization in mammalian neurons.
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