An epigenetic signature of developmental potential in neural stem cells and early neurons.

A cardinal property of neural stem cells (NSCs) is their ability to adopt multiple fates upon differentiation. The epigenome is widely seen as a read-out of cellular potential and a manifestation of this can be seen in embryonic stem cells (ESCs), where promoters of many lineage-specific regulators are marked by a bivalent epigenetic signature comprising trimethylation of both lysine 4 and lysine 27 of histone H3 (H3K4me3 and H3K27me3, respectively). Bivalency has subsequently emerged as a powerful epigenetic indicator of stem cell potential.

Repressor element 1 silencing transcription factor couples loss of pluripotency with neural induction and neural differentiation.

Neural differentiation of embryonic stem cells (ESCs) requires coordinated repression of the pluripotency regulatory program and reciprocal activation of the neurogenic regulatory program. Upon neural induction, ESCs rapidly repress expression of pluripotency genes followed by staged activation of neural progenitor and differentiated neuronal and glial genes. The transcriptional factors that underlie maintenance of pluripotency are partially characterized whereas those underlying neural induction are much less explored, and the factors that coordinate these two developmental programs are completely unknown.

Presenilins are essential for regulating neurotransmitter release.

Mutations in the presenilin genes are the main cause of familial Alzheimer's disease. Loss of presenilin activity and/or accumulation of amyloid-beta peptides have been proposed to mediate the pathogenesis of Alzheimer's disease by impairing synaptic function. However, the precise site and nature of the synaptic dysfunction remain unknown.

Indirect regulation of presenilins in CREB-mediated transcription.

Presenilins are essential for synaptic function, memory formation, and neuronal survival. Previously, we reported that expression of cAMP response element-binding protein (CREB) target genes is reduced in the cerebral cortex of presenilin (PS) conditional double knock-out (cDKO) mice. To determine whether the reduced expression of the CREB target genes in these mutant mice is due to loss of presenilin directly or secondary to the impaired neuronal activity, we established a sensitive luciferase reporter system to assess direct transcriptional regulation in cultured cells.

Hippocampal spatial memory impairments caused by the familial Alzheimer's disease-linked presenilin 1 M146V mutation.

Mutations in presenilins (PS) 1 and 2 are the major cause of familial Alzheimer's disease. Conditional inactivation of PS1 in the mouse postnatal forebrain leads to mild deficits in spatial learning and memory, whereas inactivation of both PS1 and PS2 results in severe memory and synaptic plasticity impairments, followed by progressive and substantial neurodegeneration. Here we investigate the effect of a familial Alzheimer's disease-linked PS1 missense mutation using knock-in (KI) mice, in which the wild-type PS1 allele is replaced with the M146V mutant allele.

Notch1 signaling influences v2 interneuron and motor neuron development in the spinal cord.

The Notch signaling pathway plays a variety of roles in cell fate decisions during development. Previous studies have shown that reduced Notch signaling results in premature differentiation of neural progenitor cells, while increased Notch activities promote apoptotic death of neural progenitor cells in the developing brain. Whether Notch signaling is involved in the specification of neuronal subtypes is unclear.

Regulation of CRE-dependent transcription by presenilins: prospects for therapy of Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder and is characterized by memory loss and other cognitive disabilities. Mutations in the presenilin genes are the major cause of familial AD. Analysis of conditional knockout mice has shown that inactivation of presenilins results in progressive memory impairment and age-dependent neurodegeneration, suggesting that reduced presenilin activity might represent an important pathogenic mechanism.

Neurexophilin 3 is highly localized in cortical and cerebellar regions and is functionally important for sensorimotor gating and motor coordination.

Neurexophilin 3 (Nxph3) is a specific ligand of synaptic alpha-neurexins that are essential for efficient neurotransmitter release. Previous biochemical work demonstrated that Nxph3 interacts with an extracellular domain of alpha-neurexins in a tight complex; however, no information is available on the localization or functional role of Nxph3 in the brain. Here, we generated lacZ reporter gene knock-in mice to investigate the distribution of Nxph3 at the single-cell level and Nxph3 knockout mice to examine its functional importance.

Gene-targeting technologies for the study of neurological disorders.

Studies using genetic manipulations have proven invaluable in the research of neurological disorders. In the forefront of these approaches is the knockout technology that engineers a targeted gene mutation in mice resulting in inactivation of gene expression. In many cases, important roles of a particular gene in embryonic development have precluded the in vivo study of its function in the adult brain, which is usually the most relevant experimental context for the study of neurological disorders.

Reduced beta-amyloid production and increased inflammatory responses in presenilin conditional knock-out mice.

Mutations in presenilins (PS) 1 and 2 are the major cause of familial Alzheimer's disease. Conditional double knock-out mice lacking both presenilins in the postnatal forebrain (PS cDKO mice) exhibit memory and synaptic plasticity impairments followed by progressive neurodegeneration in the cerebral cortex. Here we further investigate the molecular events that may underlie the observed phenotypes and identify additional neuropathological markers in the PS cDKO brain.