Disabled-1-regulated adhesion of migrating neurons to radial glial fiber contributes to neuronal positioning during early corticogenesis.

Disabled-1 regulates laminar organization in the developing mammalian brain. Although mutation of the disabled-1 gene in scrambler mice results in abnormalities in neuronal positioning, migratory behavior linked to Disabled-1 signaling is not completely understood. Here we show that newborn neurons in the scrambler cortex remain attached to the process of their parental radial glia during the entire course of radial migration, whereas wild-type neurons detach from the glial fiber in the later stage of migration.

Cdk5, a therapeutic target for Alzheimer's disease?

Alzheimer's disease (AD) represents the leading cause for senile dementia affecting more than 4 million people worldwide. AD patients display a triad of pathological features including brain atrophy caused by neuronal loss, beta-amyloid plaque and neurofibrillary tangles. We previously show that Cyclin-dependent kinase 5 (Cdk5) is deregulated in AD brains and may contribute to the pathogenesis of AD.

Reelin and cyclin-dependent kinase 5-dependent signals cooperate in regulating neuronal migration and synaptic transmission.

Neuronal migration and positioning in the developing brain require the coordinated interaction of multiple cellular signaling pathways. The extracellular signaling molecule Reelin and the cytoplasmic serine/threonine kinase Cdk5 (cyclin-dependent kinase 5) are both required for normal neuronal positioning, lamination of the neocortex, and foliation of the cerebellum. They also modulate synaptic transmission in the adult brain.

Cyclin-dependent kinase 5 phosphorylates the N-terminal domain of the postsynaptic density protein PSD-95 in neurons.

PSD-95 (postsynaptic density 95) is a postsynaptic scaffolding protein that links NMDA receptors to the cytoskeleton and signaling molecules. The N-terminal domain of PSD-95 is involved in the synaptic targeting and clustering of PSD-95 and in the clustering of NMDA receptors at synapses. The N-terminal domain of PSD-95 contains three consensus phosphorylation sites for cyclin-dependent kinase 5 (cdk5), a proline-directed serine-threonine kinase essential for brain development and implicated in synaptic plasticity, dopamine signaling, cocaine addiction, and neurodegenerative disorders.

Cdk5 phosphorylation of doublecortin ser297 regulates its effect on neuronal migration.

Mutations in the doublecortin (DCX) gene in human or targeted disruption of the cdk5 gene in mouse lead to similar cortical lamination defects in the developing brain. Here we show that Dcx is phosphorylated by Cdk5. Dcx phosphorylation is developmentally regulated and corresponds to the timing of expression of p35, the major activating subunit for Cdk5.

Control of cortical neuron migration and layering: cell and non cell-autonomous effects of p35.

The migration, arrest, and ultimately positioning of cortical neurons require signaling activity from Reelin as well as from cyclin-dependent kinase 5 (Cdk5). Although both molecules control neuronal positioning, they achieve their effects by quite separate molecular pathways. Cdk5 is a serine-threonine kinase, the activity of which is dependent on its activating subunits p35 and p39.

Cdk5 phosphorylation of FAK regulates centrosome-associated miocrotubules and neuronal migration.

Cdk5 is a member of the cyclin-dependent kinase (Cdk) family. Unlike other Cdks that promote cell cycle, Cdk5 is activated in postmitotic neurons and critically regulates neuronal migration by phosphorylating its substrates during brain development. Recently, we found that Cdk5 phosphorylates focal adhesion kinase (FAK) at Serine 732 in vitro and is responsible for this phosphorylation in the developing brain.

Cyclin-dependent kinase 5 and neuronal migration in the neocortex.

The cyclin-dependent kinase 5 (Cdk5) plays an important role in the proper establishment of neocortical layers. Over the past several years, key molecular targets of Cdk5 have been identified that show intriguing connections to the adhesional and cytoskeletal components of cell movement. This molecular knowledge about Cdk5 signaling has begun to translate into an understanding of how Cdk5 regulates the cellular physiology of neocortical layer formation.

Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles.

Cyclin-dependent kinase 5 (Cdk5) and its regulatory subunit p35 are integral players in the proper development of the mammalian central nervous system. Proteolytic cleavage of p35 generates p25, leading to aberrant Cdk5 activation. The accumulation of p25 is implicated in several neurodegenerative diseases.

Layering defect in p35 deficiency is linked to improper neuronal-glial interaction in radial migration.

Several genes essential for neocortical layering have been identified in recent years, but their precise roles in this process remain to be elucidated. Mice deficient in p35--an activator of cyclin-dependent kinase 5 (Cdk5)--are characterized by a neocortex that has inverted layering. To decipher the physiological mechanisms that underlie this defect, we compared time-lapse recordings between p35(-/-) and wild-type cortical slices.

BACE1 suppression by RNA interference in primary cortical neurons.

Extracellular deposition of amyloid-beta (Abeta) aggregates in the brain represents one of the histopathological hallmarks of Alzheimer's disease (AD). Abeta peptides are generated from proteolysis of the amyloid precursor proteins (APPs) by beta- and gamma-secretases. Beta-secretase (BACE1) is a type I integral membrane glycoprotein that can cleave APP first to generate C-terminal 99- or 89-amino acid membrane-bound fragments containing the N terminus of Abeta peptides (betaCTF).

APP processing is regulated by cytoplasmic phosphorylation.

Amyloid-beta peptide (Abeta) aggregate in senile plaque is a key characteristic of Alzheimer's disease (AD). Here, we show that phosphorylation of amyloid precursor protein (APP) on threonine 668 (P-APP) may play a role in APP metabolism. In AD brains, P-APP accumulates in large vesicular structures in afflicted hippocampal pyramidal neurons that costain with antibodies against endosome markers and the beta-secretase, BACE1.

Serine 732 phosphorylation of FAK by Cdk5 is important for microtubule organization, nuclear movement, and neuronal migration.

The serine/threonine kinase Cdk5 plays an essential role in neuronal positioning during corticogenesis, but the underlying mechanisms are unknown. In nonneuronal cells, the tyrosine kinase FAK is a major regulator of cell motility through focal adhesions. It is unclear whether FAK plays a role in brain development.

14-3-3epsilon is important for neuronal migration by binding to NUDEL: a molecular explanation for Miller-Dieker syndrome.

Heterozygous deletions of 17p13.3 result in the human neuronal migration disorders isolated lissencephaly sequence (ILS) and the more severe Miller-Dieker syndrome (MDS). Mutations in PAFAH1B1 (the gene encoding LIS1) are responsible for ILS and contribute to MDS, but the genetic causes of the greater severity of MDS are unknown.

Cdk5: one of the links between senile plaques and neurofibrillary tangles?

The relationship between amyloid plaques and neurofibrillary tangles, the two pathologic hallmarks of Alzheimer's disease (AD), is an unknown and controversial subject. However, emerging evidence from genetic and biochemical studies suggests that accumulation of amyloid beta peptides may play a causative role in AD pathogenesis. This led to the amyloid hypothesis, which proposes that amyloid beta peptides disrupt neuronal metabolic and ionic homeostasis and cause aberrant activation of kinases and/or inhibition of phosphatases.

Partial rescue of the p35-/- brain phenotype by low expression of a neuronal-specific enolase p25 transgene.

Cyclin-dependent kinase 5 (Cdk5) is activated on binding of activator proteins p35 and p39. A N-terminally truncated p35, termed p25, is generated through cleavage by the Ca(2+)-dependent protease calpain after induction of ischemia in rat brain. p25 has been shown to accumulate in brains of patients with Alzheimer's disease and may contribute to A-beta peptide-mediated toxicity.

The cyclin-dependent kinase 5 activators p35 and p39 interact with the alpha-subunit of Ca2+/calmodulin-dependent protein kinase II and alpha-actinin-1 in a calcium-dependent manner.

Cyclin-dependent kinase 5 (Cdk5) is a critical regulator of neuronal migration in the developing CNS, and recent studies have revealed a role for Cdk5 in synaptogenesis and regulation of synaptic transmission. Deregulation of Cdk5 has been linked to the pathology of neurodegenerative diseases such as Alzheimer's disease. Activation of Cdk5 requires its association with a regulatory subunit, and two Cdk5 activators, p35 and p39, have been identified.

A survey of Cdk5 activator p35 and p25 levels in Alzheimer's disease brains.

P25, a calpain cleavage product of the cyclin-dependent kinase 5 (Cdk5) activator p35, causes prolonged activation of Cdk5. Although p25 has been shown to accumulate in brains of patients with Alzheimer's disease (AD), it is not known whether p25 accumulation in AD is brain region-specific. We analyzed the amounts of p25 and p35 in human autopsy samples from multiple brain regions including frontal cortex, inferior parietal cortex and hippocampus using immunoblotting assays.

Colocalization and fluorescence resonance energy transfer between cdk5 and AT8 suggests a close association in pre-neurofibrillary tangles and neurofibrillary tangles.

Cyclin-dependent kinase 5 (cdk5) is a serine/threonine kinase that, when activated, induces neurite outgrowth. Recent in vitro studies have shown that cdk5 phosphorylates tau at serine 199, serine 202, and threonine 205 and that p25, an activator of cdk5, is increased in Alzheimer disease (AD). Since tau is hyperphosphorylated at these sites in neurofibrillary tangles, we examined brain tissue from patients with AD and normal elderly control cases to determine whether cdk5 and these phosphoepitopes colocalize in neurofibrillary tangles.

Life is a journey: a genetic look at neocortical development.

Although the basic principles of neocortical development have been known for quite some time, it is only recently that our understanding of the molecular mechanisms that are involved has improved. Such understanding has been facilitated by genetic approaches that have identified key proteins involved in neocortical development, which have been placed into signalling pathways by molecular and cell-biological studies. The challenge of current research is to understand the manner in which these various signalling pathways are interconnected to gain a more comprehensive picture of the molecular intricacies that govern neocortical development.

Cdk5 behind the wheel: a role in trafficking and transport?

Cdk5, a serine/threonine kinase in the cyclin-dependent kinase (Cdk) family, is an important regulator of neuronal positioning during brain development. Cdk5 might also play a role in synaptogenesis and neurotransmission. Loss of Cdk5 in mice is perinatal lethal, and overactive Cdk5 induces apoptosis in cultured cells, indicating that strict regulation of kinase activity is crucial.

Cdk5 sinks into ALS.

Recent research points to an involvement of deregulated cdk5 activity in the pathogenesis of mutant SOD1-mediated disease. In addition, inhibition of this activity might promote motor neuron survival. These observations have opened the door to further research into the role of cdk5 in ALS and other neurodegenerative diseases.

Calpain-mediated cleavage of the cyclin-dependent kinase-5 activator p39 to p29.

The activity of cyclin-dependent kinase-5 (Cdk5) is tightly regulated by binding of its neuronal activators p35 and p39. Upon neurotoxic insults, p35 is cleaved to p25 by the Ca(2+)-dependent protease calpain. p25 is accumulated in ischemic brains and in brains of patients with Alzheimer's disease.

GC box-binding transcription factors control the neuronal specific transcription of the cyclin-dependent kinase 5 regulator p35.

Cyclin-dependent kinase 5 (cdk5)/p35 kinase activity is highest in post-mitotic neurons of the central nervous system and is critical for development and function of the brain. The neuronal specific activity of the cdk5/p35 kinase is achieved through the regulated expression of p35 mRNA. We have identified a small 200-bp fragment of the p35 promoter that is sufficient for high levels of neuronal specific expression.