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Proteolipid promoter activity distinguishes two populations of NG2-positive cells throughout neonatal cortical development.

Transgenic mice expressing enhanced green fluorescent protein (EGFP) driven by the mouse myelin proteolipid protein (PLP) gene promoter have been developed to investigate cells in the oligodendrocyte lineage. Transgene expression is consistent with the developmental expression of PLP, with cells at all stages of oligodendrocyte differentiation clearly visualized. These animals were analyzed to establish the time course of oligodendrocyte progenitor migration, proliferation, and differentiation in neonatal cortex. In these animals, two populations of NG2 proteoglycan-positive oligodendrocyte progenitor cells were identified that exist in postnatal subventricular zone and cortex. These two populations are distinguished by the presence or absence of PLP gene expression. Thus, PLP gene expression defines a subpopulation of NG2-positive cells from very early postnatal ages, which migrates toward the pial surface and proliferates in situ. EGFP(+)/NG2(+) cells are present in the cortex from postnatal day 1, and they remain in the cortex as undifferentiated oligodendrocyte progenitors for up to 3 weeks before myelination begins. These data could be explained by the presence of an important inhibitor of oligodendrocyte differentiation in the cortex during this period, which is downregulated in a region-specific manner to allow myelination. On the other hand, it is possible that oligodendrocyte progenitor cells remain undifferentiated in cortex until an essential signal is produced in situ to induce differentiation.

Animals↗

Dynamics of target recognition by interstitial axon branching along developing cortical axons.

Corticospinal axons innervate their midbrain, hindbrain, and spinal targets by extending collateral branches interstitially along their length. To establish that the axon shaft rather than the axonal growth cone is responsible for target recognition in this system, and to characterize the dynamics of interstitial branch formation, we have studied this process in an in vivo-like setting using slice cultures from neonatal mice containing the entire pathway of corticospinal axons. Corticospinal axons labeled with the dye 1,1'-dioctodecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (or Dil) were imaged using time-lapse video microscopy of their pathway overlying the basilar pons, their major hindbrain target. The axon shaft millimeters behind the growth cone exhibits several dynamic behaviors, including the de novo formation of varicosities and filopodia-like extensions, and a behavior that we term "pulsation," which is characterized by a variable thickening and thining of short segments of the axon. An individual axon can have multiple sites of branching activity, with many of the branches being transient. These dynamic behaviors occur along the portion of the axon shaft overlying the basilar pons, but not just caudal to it. Once the collaterals extend into the pontine neuropil, they branch further in the neuropil, while the parent axon becomes quiescent. Thus, the branching activity is spatially restricted to specific portions of the axon, as well as temporally restricted to a relatively brief time window. These findings provide definitive evidence that collateral branches form de novo along corticospinal axons and establish that the process of target recognition in this system is a property of the axon shaft rather than the leading growth cone.

Animals↗

Adenylyl cyclase I regulates AMPA receptor trafficking during mouse cortical 'barrel' map development.

Cortical map formation requires the accurate targeting, synaptogenesis, elaboration and refinement of thalamocortical afferents. Here we demonstrate the role of Ca2+/calmodulin-activated type-I adenylyl cyclase (AC1) in regulating the strength of thalamocortical synapses through modulation of AMPA receptor (AMPAR) trafficking using barrelless mice, a mutant without AC1 activity or cortical 'barrel' maps. Barrelless synapses are stuck in an immature state that contains few functional AMPARs that are rarely silent (NMDAR-only). Long-term potentiation (LTP) and long-term depression (LTD) at thalamocortical synapses require postsynaptic protein kinase A (PKA) activity and are difficult to induce in barrelless mice, probably due to an inability to properly regulate synaptic AMPAR trafficking. Consistent with this, both the extent of PKA phosphorylation on AMPAR subunit GluR1 and the expression of surface GluR1 are reduced in barrelless neurons. These results suggest that activity-dependent mechanisms operate through an AC1/PKA signaling pathway to target some synapses for consolidation and others for elimination during barrel map formation.

Adenylyl Cyclases↗

Radial unit hypothesis of neocortical expansion.

The more than 1000-fold increase in the cortical surface without a comparable increase in its thickness during mammalian evolution can be explained in the context of the radial unit hypothesis of cortical development. Cortical expansion results from changes in the proliferation kinetics of founder cells in the ventricular zone that increase the number of radial columnar units without significantly changing the number of neurons within each unit. Thus, regulatory genes that control the timing (onset/rate/duration) and mode (symmetrical/asymmetrical) of cell divisions and the magnitude of programmed cell death (apoptosis) in the ventricular zone determine the number of cortical cells in a given species. The migration of postmitotic cells and their allocation into appropriate positions within the cortex is radially constrained by glial scaffolding and thereby creates an expanded cortical plate in the form of a sheet. Several families of genes and morphoregulatory molecules that control the production, migration and deployment of neurons within the developing cortical plate are being identified and their functions tested in vitro and in transgenic animals. The results provide a hint of how mutation of genes that regulate the early stages of corticogenesis may determine the species-specific size and basic organization of the cerebral cortex that sets the stage for the formation of the final pattern of its synaptic connections that can be validated through natural selection.

Animals↗

Frizzled9 protein is regionally expressed in the developing medial cortical wall and the cells derived from this region.

We used a newly generated antiserum specific for the Wnt receptor Frizzled9 to examine the distribution of this protein in the telencephalon. Previous studies showed expression of the mRNA for Frizzled9 in a medial high to lateral low gradient during cortical development 6. Our studies with the Frizzled9 antiserum supported this localization during mid-gestation mouse embryos. Later in gestation, the expression of Frizzled9 persisted in all cellular derivatives of the medial cortical neuroepithelium. From birth through adulthood, Frizzled9 continues to be expressed in the principal neuronal cells of the hippocampus. Interestingly, Frizzled9 was also expressed by astrocytic cells and dividing neuronal precursors in the adult dentate gyrus. Thus, Frizzled9 expression marks are a regional marker of medially derived cortical derivatives throughout rodent life and will be a useful marker in the study of regulation of cortical arealization.

Animals↗

Sex-specific development of cortical monoamine levels in mouse.

Several mental health disorders exhibit sex differences in monoamine levels associated with dimorphic cortical ontogeny. Studies in rodents support the notion that monoamines can profoundly modulate morphogenesis. Here, we show significant sex and hemisphere differences in BALB/cByJ mice on postnatal day 3 for dopamine (DA) and serotonin (5-TH), supporting the notion that sex differences in early monoaminergic ontogeny may result in dimorphic cortical development. Such sex differences may also influence differential behavioral and/or clinical outcomes.

Age Factors↗