Both Cell papers extend the cascades up- and downstream of GSK-3β considerably by providing molecular links from growth-factor signalling and cell adhesion to microtubule dynamics and axon organization—all most essential processes in evolution in "the making of a brain”!

Deficiency of the GSK-3β ortholog in Drosophila (shaggy/zeste-white 3) causes cells to adopt a neuronal phenotype as "default,” demonstrating the power that GSK-3β kinase has over neuronal development. This influence is further defined by both Cell papers. Most interesting is the appearance of a phosphatase, PTEN, among the wealth of kinases that occupy (litter?) this research field, although with its dual lipid and protein phosphatase activities, PTEN cannot be regarded as a simple addition.

Two more levels of complexity must be recognized. In addition to having its own complex molecular structures—two isozymes in mammals, at least five isoforms of shaggy in Drosophila, and four orthologs of GSK-3 in yeast—GSK-3 activity is regulated by many interacting proteins. On top of this...  Read more

Both Cell papers extend the cascades up- and downstream of GSK-3β considerably by providing molecular links from growth-factor signalling and cell adhesion to microtubule dynamics and axon organization—all most essential processes in evolution in "the making of a brain”!

Deficiency of the GSK-3β ortholog in Drosophila (shaggy/zeste-white 3) causes cells to adopt a neuronal phenotype as "default,” demonstrating the power that GSK-3β kinase has over neuronal development. This influence is further defined by both Cell papers. Most interesting is the appearance of a phosphatase, PTEN, among the wealth of kinases that occupy (litter?) this research field, although with its dual lipid and protein phosphatase activities, PTEN cannot be regarded as a simple addition.

Two more levels of complexity must be recognized. In addition to having its own complex molecular structures—two isozymes in mammals, at least five isoforms of shaggy in Drosophila, and four orthologs of GSK-3 in yeast—GSK-3 activity is regulated by many interacting proteins. On top of this comes active phosphorylation as an extra, dynamic, post-translational control mechanism.

This bewildering intricacy complicates the interpretation of "simple" experiments in mice in vivo, i.e., overexpression or knockout. Complete absence of GSK-3β in mice is lethal for the embryo, probably by suppression of anti-apoptotic actions of NF-κB (Hoeflich et al., 2000). We found that overexpression of constitutively active GSK-3β(S9A) at higher levels was also lethal early in development, while relatively low levels were viable but affected brain size by decreasing the calibre of neuronal soma and apical dendrites (Abstract42539 Spittaels et al., 2002). We noted no neurodegeneration, however, as opposed to GSK-3β transgenic mice with inducible overexpression to high levels (Lucas et al., 2001). Moreover, GSK-3β could even rescue the axonopathy of tau-4R mice, demonstrating its axonal power in vivo (Spittaels et al., 2000). Combined, the data demonstrate that GSK-3 activity needs to be regulated between narrow boundaries, and that deviation in both directions is dramatic in more than one way and in many organs and multiple systems—a heavy burden on its therapeutic potential.

Although sporadic AD must be regarded as a combination of "accidents" of which the final outcome (amyloid pathology and tauopathy) is due to a multitude of factors, the attraction of the GSK-3 isozymes is their potential to affect both types of pathology, thus providing one trigger… Whether GSK-3α/β isoforms are "accidents" themselves is not clear yet, but likely they are vulnerable partners in the complex signalling cascade outlined by both Cell papers. As part of these cascades, Cdk5 as a priming kinase for GSK-3β does not really explain or help us understand the contributions of either kinase to the tauopathy in AD, but it does reaffirm the link between the two proteins in this respect. We await the final answer: What triggers them to do what they do in aging brain, causing MCI and AD?

View all comments by Fred Van Leuven

1136 In the last issue of Cell, Jiang et al. and Yoshimura et al. have published two excellent articles about the role of GSK3 in determining neuronal polarity.

In most cases, a neuron has a single axon and several dendrites. This type of neuronal polarity is very important for neural network function where signal transmission goes from the axon to the dendrites.

Changes in two cytoskeletal structures, microfilaments and microtubules, have been involved in the establishment of neural polarity. The work of several groups like those of Dotti or Matus has been focused on the role of microfilaments, whereas many other groups have studied the role of microtubules, mainly that of tubulin-binding proteins, in the development of neuronal polarity.

In the first paper, Jiang et al. described the importance of a kinase, GSK3, and a phosphatase, PTEN, in facilitating axonogenesis. In the second paper, Yoshimura et al. have looked for a GSK3 substrate that could be involved in axonogenesis. They found that such a substrate was the tubulin-binding protein CRMP-2, and that CRMP-2...  Read more

1136 In the last issue of Cell, Jiang et al. and Yoshimura et al. have published two excellent articles about the role of GSK3 in determining neuronal polarity.

In most cases, a neuron has a single axon and several dendrites. This type of neuronal polarity is very important for neural network function where signal transmission goes from the axon to the dendrites.

Changes in two cytoskeletal structures, microfilaments and microtubules, have been involved in the establishment of neural polarity. The work of several groups like those of Dotti or Matus has been focused on the role of microfilaments, whereas many other groups have studied the role of microtubules, mainly that of tubulin-binding proteins, in the development of neuronal polarity.

In the first paper, Jiang et al. described the importance of a kinase, GSK3, and a phosphatase, PTEN, in facilitating axonogenesis. In the second paper, Yoshimura et al. have looked for a GSK3 substrate that could be involved in axonogenesis. They found that such a substrate was the tubulin-binding protein CRMP-2, and that CRMP-2 phosphorylation by GSK3 is regulated by trophic factors. In the absence of GSK3 activity, CRMP-2 binds to microtubules, which are stabilized. The consequence of that microtubule stabilization is the cytoplasmic extension that results in the formation of an axon. Thus, the whole axonogenesis mechanism from the ligand (trophic factor) to the morphological change (axonogenesis) could be explained.

These two important observations complement the previous ones on the role of MAP1B, and its modification by GSK3, in axon formation, revealed by several groups like, among others, those of Hirokawa, Edelman, Probst, Salinas, Gordon-Weeks, Fisher, and ourselves. Similar studies on the role of tau protein and also its modification by GSK3 were done by our group and those of Anderton and Bhat, among others. Also, those observations may suggest the use of GSK3 inhibitors for axonal regeneration.

However, there are yet some questions that remain to be answered, such as why a typical neuron has a single axon and many dendrites.

View all comments by Jesus Avila

I think these are very interesting papers from the AD point of view, especially since PS1 is involved in the PI3K/Akt pathway which regulates GSK3 and its downstream target CRMP-2. Specifically it has been shown (see Baki et al., 2004) that PS1 downregulates the activity of GSK3β by stimulating the PI3K/Akt pathway. FAD mutations interfere with the function of PS1 in the PI3K/Akt signaling and this results in upregulation of GSK3β and tau overphosphorylation (Baki et al., 2004).

Since PS1 regulates the PI3K signaling and GSK3 activity, the findings of the Cell papers imply that PS1 may also affect the activity of CRMP-2 (See fig. 7 in Kaibuchi's paper, reproduced above) and this suggests (although it does not prove) that PS1 may also be involved in determining neuronal polarity. Other labs, including that of Dr. Takashima, have also shown that PS1 regulates GSK3 activity.

On the other hand, I find the suggestion of a linkage between CRMP-2 and NFTs a little premature, but reasonable.

View all comments by Nikolaos K. Robakis