Cyclin-dependent kinase 5 (Cdk5) is a nontraditional Cdk that is primarily active in postmitotic neurons. Its best known substrates are cytoskeletal proteins. Less appreciated is its role in the maintenance of a postmitotic state. We show here that in cycling cells (NIH 3T3), the localization of Cdk5 changes from predominantly nuclear to cytoplasmic as cells reenter a cell cycle after serum starvation. Similarly, when -amyloid peptide is used to stimulate cultured primary neurons to reenter a cell cycle, they too show a loss of nuclear Cdk5. Blocking nuclear export pharmacologically abolishes cell cycle reentry in wild-type but not Cdk5 ؊/؊ neurons, suggesting a Cdk5-specific effect. Cdk5 overexpression targeted to the nucleus of Cdk5 ؊/؊ neurons effectively blocks the cell cycle, but cytoplasmic targeting is ineffective. Further, in both human Alzheimer's disease as well as in the R1.40 mouse Alzheimer's model and the E2f1 ؊/؊ mouse, neurons expressing cell cycle markers consistently show reduced nuclear Cdk5. Thus, both in vivo and in vitro, neurons that reenter a cell cycle lose nuclear Cdk5. We propose that the nuclear Cdk5 plays an active role in allowing neurons to remain postmitotic as they mature and that loss of nuclear Cdk5 leads to cell cycle entry.Alzheimer's disease ͉ -amyloid precursor protein transgenic mice ͉ cell cycle ͉ E2F1 ͉ neurodegeneration
The mouse homeodomain protein, Engrailed-1, is generally viewed as an essential player in the early establishment and maintenance of the midbrain/hindbrain region that gives rise to the cerebellum and midbrain. In keeping with this, engineered null mutations at this locus have been reported to lead to perinatal lethality accompanied by near-total absence of cerebellar and caudal midbrain structures. We report here that these cerebellar phenotypes are nearly completely suppressed on a C57BL/6J genetic background. All cell types are present and arranged properly in both the cortex and the deep nuclei, and cell counts reveal no significant absence of cerebellar Purkinje cells. Folial patterns are nearly normal, although an apparent fusion of lobules IV and V is consistently noted. Significantly, no change in the Engrailed-2 mutant phenotype occurs after a similar background switch, and whole-mount in situ hybridization reveals identical En2 expression patterns in wild-type C57BL/6J and 129/Sv mice. One likely mechanism for the En1-/- phenotype suppression is a temporal and/or spatial change in the pattern of Engrailed-2 expression apparent only in the absence of Engrailed-1. In support of this, C57BL/6-En1-/- embryos that are also En2+/- lack a cerebellum and caudal midbrain: a phenotype identical to 129/Sv-En1-/- mice.
Alzheimer's disease is late life dementia associated with significant neurodegeneration in both cortical and subcortical regions. During the ϳ10 year course of the disease, neurons are lost in a progressive pattern that is relatively consistent among individuals. One example of this is the progression of disease pathology found in both the neocortex and archicortex. In these structures, the earliest problems can be found in superficial cortical layers (II-IV), whereas later the disease advances to involve the deeper cortical layers (V-VI). It is unclear whether these apparent differences in sensitivity are intrinsic to the neurons or imposed by external factors such as the pattern of connections. We used -amyloid (A) peptide treatment of cultured mouse neurons as our model system. We show first that, as in hippocampus, dissociated cultures of embryonic cortical neurons are biased toward the survival of cells that were finishing division in the ventricular zone at the time of harvest. Thus, embryonic day 13.5 (E13.5) cultures contain primarily deep-layer neurons whereas E16.5 cultures contain cells destined for upper layers. We use this cell-type specific segregation to our advantage and show, using both differences in gene expression profiles and A survival curves, that deeper layer neurons are significantly more resistant to the toxic effects of A than are cells from the more superficial strata. This suggests that an intrinsic underlying biology drives at least part of the AD progression pattern and that the time of harvest is a crucial variable in the interpretation of any cortical culture experiment.
Little is known about the genetic pathways and transcription factors that control development and maturation of central auditory neurons. En1, a gene expressed by a subset of developing and mature superior olivary complex (SOC) cells, encodes a homeodomain transcription factor important for neuronal development in the midbrain, cerebellum, hindbrain and spinal cord. Using genetic fate-mapping techniques, we show that all En1-lineal cells in the SOC are neurons and that these neurons are glycinergic, cholinergic and GABAergic in neurotransmitter phenotype. En1 deletion does not interfere with specification or neural fate of these cells, but does cause aberrant positioning and subsequent death of all En1-lineal SOC neurons by early postnatal ages. En1-null cells also fail to express the transcription factor FoxP1, suggesting that FoxP1 lies downstream of En1. Our data define important roles for En1 in the development and maturation of a diverse group of brainstem auditory neurons.
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