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Cell Growth & Differentiation Vol. 12, 277-283, June 2001
© 2001 American Association for Cancer Research


Review

Cdk5 on the Brain

Deanna S. Smith1, Paul L. Greer and Li-Huei Tsai

Department of Pathology [D. S. S., P. L. G., L-H. T.] and Howard Hughes Medical Institute [L-H. T.], Harvard Medical School, Boston, Massachusetts 02115


    Abstract
 TOP
 Abstract
 Introduction
 Neuronal Migration
 Axon Growth and Pathfinding
 Extracellular Signals and Cdk5...
 Downstream Effector Systems
 Cdk5 in Disease
 Parallels between Cdk5 and...
 References
 
Mammalian brains are highly compartmentalized into groups of functionally specialized neurons. Cell migration and neurite outgrowth must be tightly orchestrated to achieve this level of organization. A small serine/threonine kinase that shows homology to cyclin-dependent kinases (Cdks) has emerged as an important regulator of neuronal migration. Cdk5, unlike other Cdks, is not regulated by cyclins, and its activity is primarily detected in postmitotic neurons in developing and adult nervous systems. This review describes work indicating that Cdk5 links extracellular signaling pathways and cytoskeletal/membrane systems to direct neuronal migration, axon growth, and possibly neurosecretion. Despite its importance, unchecked Cdk5 activity is toxic to neurons, and may underlie some of the pathologies associated with neurodegenerative disorders such as Alzheimer’s disease and amyotrophic lateral sclerosis.


    Introduction
 TOP
 Abstract
 Introduction
 Neuronal Migration
 Axon Growth and Pathfinding
 Extracellular Signals and Cdk5...
 Downstream Effector Systems
 Cdk5 in Disease
 Parallels between Cdk5 and...
 References
 
DNA replication and cell division must be tightly regulated during embryogenesis to produce a viable organism. Kinases that are activated by cyclin family members (Cdks2 ) play a critical role in orchestrating transitions through the cell cycle in a variety of species. Much of the early characterization was done in yeast systems (1) , where cdc2 in Schizosaccharomyces pombe and cdc28 in Saccharomyces cerivisiae are required for the both G1-to-S and G2-to-M transitions. A large family of Cdks (10 or more members in humans) has been discovered in vertebrates, and most of them orchestrate cell cycle transitions (2, 3, 4, 5, 6) . Cdk1 (the mammalian counterpart to Cdc2/cdc28) is a critical regulator of cell division, whereas Cdk2 and Cdk4 control the timing of DNA replication. Most Cdk family members are activated upon association with regulatory subunits called cyclins. There are at least 15 cyclin genes in the human genome. When activated, Cdks phosphorylate serine and threonine residues in a proline-directed fashion.

Only a few Cdk family members have roles outside the cell cycle. One of these is Cdk5, a protein that shows 60% homology to Cdk1 (5 , 6) . In mammals, Cdk5 mRNA and protein are expressed in kidney, testes, and ovary, but by far the highest level of expression is in postmitotic neurons in developing and adult nervous systems (7 , 8) . Although Cdk5 is present in other tissues, activity is detected almost exclusively in brain extracts.

Similar to other Cdks, monomeric Cdk5 displays no enzymatic activity, but Cdk5 is not activated by cyclins. Instead, Cdk5 activity requires association with one of two brain-specific regulatory subunits called p35 and p39 (9, 10, 11, 12) . These regulatory partners bear little sequence similarity to cyclins, although structural studies suggest that p35 assumes a cyclin-like fold (11 , 13 , 14) .

Over the last decade, progress has been made in elucidating the role of Cdk5 in the brain. The best-studied role for Cdk5 is in regulating neuronal migration, but there is also evidence to link Cdk5 activity to axon growth and synaptic function. In addition, p35/Cdk5 functions in muscle cells at the neuromuscular junction, and functional orthologues of p35/Cdk5 in yeast regulate endocytosis and actin dynamics. Fig. 1Citation shows several signaling pathways influenced by Cdk5 activity and points to the effector systems regulated by these pathways. Known or suspected Cdk5 substrates identified to date are listed in Table 1Citation . The following sections will describe each pathway and many of the substrates in more detail.



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Fig. 1. Cdk5 and its activating partner, p35, may be a point of integration for extracellular signals regulating neuronal migration. In this model, lines indicate published interactions between proteins and connect signaling pathways to known downstream events involving cytoskeletal or membrane systems. These or other potential pathways may lead to changes in gene expression, but this is not a well-studied area and has not been included in the model.

 

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Table 1 Cdk5 substrates and their subcellular affiliations

 
It is becoming clear that deregulated Cdk5 activity is neurotoxic and has been linked to neurodegenerative diseases such as Alzheimer’s disease. This review focuses on several key findings that add to our understanding of this fascinating kinase.


    Neuronal Migration
 TOP
 Abstract
 Introduction
 Neuronal Migration
 Axon Growth and Pathfinding
 Extracellular Signals and Cdk5...
 Downstream Effector Systems
 Cdk5 in Disease
 Parallels between Cdk5 and...
 References
 
Evidence of the involvement of Cdk5 in neuronal migration came from analysis of mice with homozygous deletions in the p35 and Cdk5 genes (15 , 16) . Loss of p35 caused a remarkable inversion of the normal laminar pattern of neurons in the cerebral cortex. In the normal cortex, neurons are organized into six distinct layers. Newly postmitotic neurons migrate to form these layers along one of several migratory routes, depending on the location of the proliferative neuroepithelium from which they differentiated. The most well-studied route is exhibited by neurons born in epithelium lining the lateral ventricles (ventricular zone; Ref. 17 ). These neurons migrate radially outward along glial processes that extend the width of the developing cortex. Neurons detach from the glia to populate the developing cortical plate in an "inside out" fashion. That is, neurons in the outermost layers migrate through previously formed layers to reach their final destination. In p35-/- mice, the layering pattern is inverted; later-born neurons appear to pile up under earlier waves of migrating cells. Inverted cortical layering is also observed in two spontaneous mutant strains known as reeler and scrambler. The p35-/- phenotype is less severe, however, because reeler and scrambler display migration defects outside the cortex.

Although p35-/- mice are particularly susceptible to seizures and early lethality, they are fertile and can live into adulthood. Cdk5 knockouts, on the other hand, die in late embryogenesis or at birth, demonstrating that p35 alone cannot account for all Cdk5-dependent phosphorylation events. Cortical lamination is also severely disrupted in Cdk5-/- mice, but the brain defects are much more widespread than in p35 knockouts. The migration defect caused by loss of Cdk5 in cerebellar neurons was shown to be cell autonomous, indicating that Cdk5 needs to be functioning in the migrating cells (18) . Mice with mutations in the other known partner of Cdk5, p39, exhibit no overt brain abnormalities, whereas mice deficient in both p35 and p39 die perinatally with the same severe brain abnormalities as observed in Cdk5-/- mice.3 Thus, p35 and p39 together are necessary and sufficient for regulated Cdk5 activity during nervous system development. Expression patterns of p39 and p35 are overlapping but distinct. Also, p39 contains a 30-amino acid insert in the COOH-terminal region of the protein. The proteins are very similar over the remainder of their sequences (19, 20, 21, 22) . It is not clear whether p35 and p39 bestow different substrate specificities, but cell fractionation experiments suggest they may reside in distinct subcellular locations (12 , 23) . The fact that p39-/- mice display no defects in brain development argues that p35 can substitute for a deficiency in p39.


    Axon Growth and Pathfinding
 TOP
 Abstract
 Introduction
 Neuronal Migration
 Axon Growth and Pathfinding
 Extracellular Signals and Cdk5...
 Downstream Effector Systems
 Cdk5 in Disease
 Parallels between Cdk5 and...
 References
 
p35-/- and Cdk5-/- mice have defects in fasciculation in several prominent axon tracts (24) . Although this could be a secondary consequence of aberrant neuronal positioning, several lines of evidence point to a direct role for Cdk5 activity in axons: (a) both Cdk5 and p35 are present in axon shafts and growth cones, the migratory tips of growing axons (25) ; (b) cultured neurons in which Cdk5 activity is inhibited show a decreased capacity to grow or maintain axonal projections (25) ; and (c) loss-of-function experiments in Drosophila point to a role for Cdk5 in axon targeting (26) . Some of the cellular processes important during cell migration may also be regulated in growth cone migration. Indeed, migrating neurons in the cortex extend "leading processes" that resemble growing axons (27) . The need for Cdk5 activity in axons and migrating neurons may reflect the similarities inherent in these processes.


    Extracellular Signals and Cdk5 Activity
 TOP
 Abstract
 Introduction
 Neuronal Migration
 Axon Growth and Pathfinding
 Extracellular Signals and Cdk5...
 Downstream Effector Systems
 Cdk5 in Disease
 Parallels between Cdk5 and...
 References
 
Cadherin Pathways.
Cadherins are a family of homophilic, calcium-dependent adhesion molecules, many of which are expressed in the developing nervous system. Reduction of cadherin-mediated adhesion has been linked to neural crest migration and the acquisition of metastatic characteristics in cancer cells (28) . Cdk5 interacts with ß-catenin, a protein that associates with the cytoplasmic tails of cadherins and stabilizes the receptors at the plasma membrane, probably by virtue of its interaction with the actin cytoskeleton through {alpha}-catenin (29) . Modulation of Cdk5 activity in neurons alters their adhesive properties in a calcium-dependent fashion, and increased activity dissociates ß-catenin from N- cadherin, leading to loss of adhesion (30) . Cdk5 phosphorylates ß-catenin in vitro, which may be the event that causes it to leave the cadherin complex (31) . The regulation of adhesion is likely to figure prominently in the migration of neurons along glial or axonal fibers, as well as in their movement through previously formed layers.

Non-Receptor Tyrosine Kinases.
Non-receptor tyrosine kinases function downstream of a wide range of receptor types. Interestingly, Cdk5 associates with one of these, c-Abl, through a linker protein, Cables (32) . This association promotes phosphorylation of Cdk5 by c-Abl on tyrosine 15. Phosphorylation is an activating event for Cdk5, whereas phosphorylation on the equivalent tyrosine residues is inhibitory to other Cdks.

Analysis of Drosophila mutants has uncovered genetic pathways involving the Drosophila orthologue of c-Abl, DAbl. DAbl is abundant in axons, but mutations do not effect embryonic central nervous system development (33) . DAbl interacts genetically with another protein, disabled (Dab). Loss of Dab in a DAbl heterozygous background leads to embryonic lethality and defects in axon organization and fasciculation (34) . In Drosophila, Notch signaling cooperates with D-Abl kinase activity in growth cone motility, probably through the recruitment of Dab (35) . Dab may regulate growth cone behavior by virtue of its interactions with Rac and a RacGEF called Trio (36) .

Mutations in the murine homologue of Dab, mDab1, are responsible for the scrambler phenotype in mice, and Reelin, an extracellular matrix-like molecule, is mutated in the reeler mouse (see references in Ref. 38 ). These pathways have now been linked through two receptors, VLDLR and ApoER2 (37, 38, 39 , 41) . Compound loss of both VLDLR and ApoER2 produces cortical lamination phenotypes indistinguishable from mDab1 knockouts, and mDab1 associates with the cytoplasmic tails of VLDLR and ApoE2R. Reelin has also been linked to signaling through cadherin-related neuronal receptors (42) and integrins (43) . Integrins have been shown to influence p35/cdk5 activity and distribution (44, 45, 46) , and Cdk5 can phosphorylate c-src, a non-receptor tyrosine kinase that acts downstream of integrin signaling at adhesion plaques (47) .

Taken together, the findings to date point to a large degree of cross-talk between events downstream of distinct extracellular signals and suggest that orchestrating signaling through these receptor systems may be one of the roles of Cdk5. As is the case with cadherins, however, Cdk5 seems to regulate the receptors themselves and as such must be considered "upstream" of receptor mediated-signaling.


    Downstream Effector Systems
 TOP
 Abstract
 Introduction
 Neuronal Migration
 Axon Growth and Pathfinding
 Extracellular Signals and Cdk5...
 Downstream Effector Systems
 Cdk5 in Disease
 Parallels between Cdk5 and...
 References
 
Neuronal migration involves coordinated changes in adhesion and polarity and the extension of a "leading process." The cytoskeleton reorganizes, motors are activated, and the direction of membrane movement changes. Analysis of Cdk5 interactions and potential substrates has begun to uncover roles for Cdk5 that impinge on many of these systems.

Actin Cytoskeleton.
Actin dynamics are thought to underlie some of the cell shape changes required for migratory behavior (43) . c-Abl and integrin signaling, both of which are linked to Cdk5 activity, can cause alterations in the actin cytoskeleton through interactions with the Rho family of GTPases (48 , 49 , 50) . Interestingly, p35 associates directly with the one of these proteins, Rac, in a GTP-dependent manner. A Rac effector, Pak1 kinase, is also present in Rac-p35/Cdk5 complexes in neurons. Active p35/Cdk5 kinase causes Pak1 hyperphosphorylation in a Rac-dependent manner. This inhibits Pak1 kinase activity, which influences actin dynamics in neurons (51) . p35 and p39 colocalize with actin in transfected cells and neurons (12 , 25) , further suggesting a role for Cdk5 in actin dynamics.

Neurofilaments.
In nonneuronal cells, intermediate filaments may modulate migratory behavior through interactions with desmosomes (52) . The intermediate filament network in neurons is mainly composed of dynamic polymers called neurofilaments (53) . Three subunits of different sizes, designated NFH, NFM, and NFL, form neurofilament polymers. NFM and NFH contain proline-directed phosphorylation sites that consist of the repeat sequence motif, Lys-Ser-Pro (KSP). Many of these have a good consensus sequence for Cdk5 (KSPXK/R). Indeed, NFH can be phosphorylated by Cdk5 (54) . Neurofilaments play a well-established role in the control of axon caliber, and there is growing evidence that they can affect the dynamics of microtubules and actin filaments (53) . Neurofilaments are transported in axons by microtubule motors (55 , 56) , although there is substantial controversy as to the nature and regulation of transport. Although neurofilaments can move rapidly, they spend 80–95% of their time in axons not moving; more highly phosphorylated pools are less mobile, suggesting that phosphorylation may slow transport (57) . Overexpression of p25, a potent, p35-derived activator of Cdk5, causes cytoskeletal changes that suggest defective transport (58) . Interestingly, the spinal cords of Cdk5-/- mice accumulate neurofilaments in motor neuron cell bodies, suggesting that loss of activity may also affect transport(16) and arguing that precise regulation of kinase activity is critical for normal cellular function.

Microtubules and Motors.
Microtubules are dynamic polymers intimately involved in the regulation of cell shape and motility. Several lines of evidence link Cdk5 to the microtubule network. The neuronal microtubule-associated proteins MAP-2, MAP1b, and tau are substrates for Cdk5 phosphorylation (44 , 59) . The role of phosphorylation by Cdk5 is not known for these proteins, but phosphorylated tau shows reduced binding to microtubules, which could lead to decreased bundling of these structures (see references in Ref. 60 ).

Cadherin signaling has been recently linked directly to microtubule organization in centrosome-free cytoplasts (61) . ß-Catenin interacts with adenomatous polyposis coli (APC), one of a growing number of proteins that cap plus ends polarized microtubules (62) . APC is expressed at high levels in the developing nervous system and may be linked to migration and metastatic potential in cancer cells (63) . The fact that Cdk5 phosphorylates ß-catenin raises intriguing possibilities that Cdk5 could impact microtubule dynamics by this mechanism.

More exciting still is the recent discovery that Cdk5 may regulate the behavior of a microtubule motor, cytoplasmic dynein, through phosphorylation of a protein called Nudel (64 , 65) . Axonemal dynein motors function in flagellar movements (66) , whereas cytoplasmic dynein contributes to a wide range of processes, including axonal transport of organelles and microtubules (67) . Nudel is expressed at high levels in the brain where it associates with dynein motors. Nudel also serves as a Cdk5 substrate in vitro and in vivo. A nonphosphorylatable mutant of Nudel introduced into cultured neurons causes axons to develop prominent swellings (60) similar to those observed when dynein function is disrupted in Drosophila neurons (68) . It is likely that overexpression of nonphosphorylatable Nudel interferes with axonal transport.

Nudel was originally isolated in yeast two-hybrid screens using the Lis1 protein as bait (60 , 64) . Lis1 is linked to neuronal migration through genetic analyses of human haploinsufficiency syndromes that present a neuronal migration defect classified as type 1 lissencephaly (64 , 70) . Lis1 also interacts with dynein, and modulation of levels has a dramatic influence on microtubule organization and dynein behavior (65) . Thus, through Lis1, Nudel, and Cdk5, dynein motor proteins have been linked to neuronal migration.

Synaptic Functions and Membrane Cycling.
The lowered threshold for lethal seizures in p35-/- mice indicates that the kinase may play a role in synaptic function. Cdk5, p39, and p35 are present in subcellular fractions enriched for synaptic membranes (23 , 60) , and p39 was shown by immunogold labeling to localize to pre- and postsynaptic compartments (23) . On the basis of these findings, it is not surprising that substrates for Cdk5 have been found among proteins that function at synapses. For example, Cdk5 has been implicated in postsynaptic signaling events triggered by the neurotransmitter dopamine through the cyclic AMP-regulated phosphoprotein, DARPP-32 (71) . Spiny neurons in the nucleus accumbens that contain DARPP-32 also contain Cdk5, and dendrites of these cells contained puncta of immunoreactivity to both proteins. Cdk5-dependent phosphorylation of DARPP-32 reduces the efficacy of dopamine signaling. Exciting results published recently suggest that changes in Cdk5 levels mediated by {Delta}FosB, and the resulting alterations in signaling involving D1 dopamine receptors contribute to adaptive changes in the brain related to cocaine addiction (72) .

In addition to dopamine signaling, Cdk5 may regulate aspects of neurosecretion and endocytosis through interactions with synaptic vesicle and membrane proteins. Synapsin1, a major phosphoprotein of synaptic terminals, can serve as a substrate for Cdk5 (73) . Munc-18, a synaptic protein involved in vesicle release is also phosphorylated by Cdk5 (74) , as is amphiphysin1, a protein linked to vesicle endocytosis (75) . Analysis of a functional homologue of Cdk5 in budding yeast, Pho85, suggests an evolutionarily conserved role for Cdk5 in membrane dynamics (76 , 77) . Pho85 has been linked to several processes in yeast, among them endocytosis through phosphorylation of the yeast equivalent of amphiphysin1. Human Cdk5 expressed in yeast was activated by the Pho85 partners Pho80 and Pcl and complemented most phenotypes associated with Pho85 defects. In a reciprocal manner, Pho85 associated with p35 to form an active kinase complex in mammalian and insect cells.

Although p35/Cdk5 activity is primarily associated with neurons, there is evidence for a role in neuregulin-induced acetylcholine receptor expression at the postsynaptic neuromuscular junction (78) . Neuregulin increases Cdk5 expression and activity in cultured myotubes, where it associates with and phosphorylates Erb receptors leading to increased acetylcholine receptor expression. Cdk5 had earlier been shown to function, along with a novel activating partner, in regulating muscle differentiation in Xenopus (79) . Whether the kinase will have roles in other tissues has yet to be determined.


    Cdk5 in Disease
 TOP
 Abstract
 Introduction
 Neuronal Migration
 Axon Growth and Pathfinding
 Extracellular Signals and Cdk5...
 Downstream Effector Systems
 Cdk5 in Disease
 Parallels between Cdk5 and...
 References
 
Alzheimer’s Disease.
Subcellular localization and stability of p35 are highly regulated, suggesting that Cdk5 kinase activity needs to be tightly controlled. Cdk5 hyperactivity is toxic to cultured neurons and may underlie neurodegeneration associated with diseases like Alzheimer’s disease (80) . Hyperactivity can be conferred by catalytic cleavage of p35 by the calcium-activated protease, calpain, resulting in a more stable isoform, p25 (80, 81, 82) . When overexpressed in neurons and other cells, p25 is considerably more toxic than p35. In addition to being more stable, p25 is missing a myristoylation signal present in p35 and as a consequence does not localize to membranes (80) . Indeed, p35 overexpressed in cultured neurons distributes to growth cones, whereas p25 does not; therefore, kinase activity may also be mislocalized in the presence of excess p25. A striking finding that supports the link between p25 and toxicity is its increased presence in brain extracts from patients with Alzheimer’s disease (80) . Calpains, too, are implicated in Alzheimer’s disease, especially after changes in calcium homeostasis caused by a variety of insults (83 , 84) . Although there might be a role for p25 in normal brain function, production of p35 may occur only under pathological conditions that trigger calpain activity. On the other hand, activation of calpain has been linked to integrin-mediated cell spreading and migration in nonneuronal cells (85) . Future experiments will be needed to differentiate between these possibilities.

What are the consequences of deregulated Cdk5 activity in Alzheimer’s disease? An obvious candidate for hyperphosphorylation is the Cdk5 substrate tau. Hyperphosphorylated tau forms the paired helical filaments found in neurofibrillary tangles, which, along with amyloid plaques, are a major hallmark of Alzheimer’s disease. Tau becomes hyperphosphorylated in p25-overexpressing transgenic mice that show Alzheimer’s-like lesions (58) . p25 overexpression also causes tau hyperphosphorylation and triggers neuritic dystrophy in cultured neurons (80) .

Another candidate for hyperphosphorylation is ß-catenin, based on its interactions with a protein called presenilin-1. Mutations in the presenilin-1 gene are a major cause of familial, early-onset Alzheimer’s disease. In transgenic mice, pathogenic mutations in presenilin-1 reduce the ability of presenilin-1 to interact with and stabilize ß-catenin, leading to increased degradation of this protein (86) . Also, ß-catenin levels are reduced in the brains of Alzheimer’s disease patients with presenilin-1 mutations. Finally, p35/Cdk5 can influence the association of presenilin-1 and ß-catenin by its phosphorylation of ß-catenin (31) , suggesting that this pathway, if deregulated, could be toxic.

ALS.
ALS is a common, adult-onset, neurodegenerative disease characterized by loss of motor neurons in the brain and spinal cord, leading to muscle atrophy, paralysis, and death 2–5 years after onset (53 , 87) . Motor neurons are unique because of their large-caliber axons, a characteristic that is dependent on neurofilaments. One of the hallmarks of ALS is the accumulation of phosphorylated neurofilaments in the cell bodies and proximal axons of motor neurons, similar to that found in Cdk5-/- mice (16) . Neurofilaments are transported by microtubule motors into axons, and in mice carrying mutations known in familial ALS patients, axonal transport defects appear long before neuronal degeneration (88) .

A few sporadic cases of ALS have been linked to neurofilament mutations mapping to the repetitive KSP region (87) . The ability of Cdk5 to phosphorylate this region has led to speculation on its role in progression of the disease. Antibodies recognizing Cdk5-phosphorylated NF epitopes label aggregates of NF in diseased motor neurons. Aggregates are also produced when NFH is overexpressed, but amazingly, this prolongs the life of mice carrying mutations in SOD1, a gene demonstrated to be causative in many familial cases of ALS (89) . Nyugen et al. (90) have now shown that p25 accumulates in these mice, and they propose that NF accumulation may actually be a protective agent in the disease, possibly serving as a phosphorylation sink for overactive Cdk5, preventing pathologies associated with hyperphosphorylated tau protein (90) . Indeed, tau hyperphosphorylation is inversely correlated to somal NF accumulation.


    Parallels between Cdk5 and Other Cdks
 TOP
 Abstract
 Introduction
 Neuronal Migration
 Axon Growth and Pathfinding
 Extracellular Signals and Cdk5...
 Downstream Effector Systems
 Cdk5 in Disease
 Parallels between Cdk5 and...
 References
 
Although a major concern in the development of multicellular organisms is cell migration and differentiation, the construction of a multicellular system also depends on cell multiplication. A vast body of literature concerns the role of Cdks in orchestrating DNA synthesis and mitosis, a process that involves motors, changes in cell adhesion, and cytoskeletal rearrangements. Sound familiar? With its wide sphere of influence, Cdk5 resembles other Cdks that orchestrate the assortment of events required during cell proliferation. Also, similar to other Cdks, deregulated Cdk5 activity can cause disease, but whereas deregulation of most Cdks results in cancerous growth, unchecked Cdk5 causes neurodegeneration.


    Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 To whom requests for reprints should be addressed, at Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115. Phone: (617) 432-0320; Fax: (617) 432-3975; E-mail: deanna_smith{at}hms.harvard.edu Back

2 The abbreviations used are: Cdk, cyclin-dependent kinase; NFH, neurofilament heavy chain; NLM, neurofilament medium chain; NFL, neurofilament light chain; ALS, amyotrophic lateral sclerosis. Back

3 J. Ko, personal communication. Back

Received for publication 4/13/01. Accepted for publication 4/16/01.


    References
 TOP
 Abstract
 Introduction
 Neuronal Migration
 Axon Growth and Pathfinding
 Extracellular Signals and Cdk5...
 Downstream Effector Systems
 Cdk5 in Disease
 Parallels between Cdk5 and...
 References
 

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