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AMPK signaling in neuronal polarization: Putting the brakes on axonal traffic of PI3-Kinase.

Amato S, Man HY - Commun Integr Biol (2012)

Bottom Line: Our recent work shows that activity of the AMP-activated protein kinase (AMPK), the bio-energy sensor responsible for maintaining cellular energy homeostasis in all eukaryotic cells, plays an important role in the initiation of axonal growth.The mislocation of PI3K, which is normally enriched at the axonal tip for extension and differentiation, results in a lack of neurite specification and neuron polarization.These findings reveal a link between cellular bioenergy homeostasis and neuron morphogenesis, and suggest a novel cellular mechanism underlying the long-term neurological abnormalities as a consequence of bioenergy deficiency during early brain development.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology; Boston University; Boston, MA USA.

ABSTRACT
Neuronal polarization, the process by which neurons form multiple dendrites and an axon from the soma, is the first critical step in the formation and function of neural networks. Polarization begins with the rapid extension of a single neurite to produce an axon of impressive size and complex geometry, while the remaining sister neurites differentiate into dendrites. The extensive biosynthesis required to produce an axon therefore necessitates coordination with cellular energy status to ensure an ample energy supply. Our recent work shows that activity of the AMP-activated protein kinase (AMPK), the bio-energy sensor responsible for maintaining cellular energy homeostasis in all eukaryotic cells, plays an important role in the initiation of axonal growth. AMPK phosphorylates the cargo-binding light chain of the Kif5 motor protein, leading to dissociation of the phosphatidylinositol 3-Kinase (PI3K) from the motor complex. The mislocation of PI3K, which is normally enriched at the axonal tip for extension and differentiation, results in a lack of neurite specification and neuron polarization. These findings reveal a link between cellular bioenergy homeostasis and neuron morphogenesis, and suggest a novel cellular mechanism underlying the long-term neurological abnormalities as a consequence of bioenergy deficiency during early brain development.

No MeSH data available.


Related in: MedlinePlus

Figure 1. Schematic illustration depicting the mechanism of AMPK dependent polarity inhibition. (A) Under normal energy conditions AMPK exists in an unphosphorylated/inactive state and PI3K is transported to the neurite tip via a physical association with the kif5 cargo adaptor, KLC. The accumulation of PI3K at a single neurite tip promotes the signaling responsible for axon initiation and growth. (B) Under energy-lacking conditions, AMP binds to AMPK producing a conformational change in the kinase, allowing phospho-activation of AMPK by upstream kinases (AMPKK). AMPK-caused KLC phosphorylation dissociates PI3K, resulting in a loss of PI3K from the neurite tip and an inhibition of neuronal polarization. (C) Cultured hippocampal neurons are transfected with GFP for visualization. Control neuron shows typical single axon (left), which is missing in a neuron treated with AMPK activator AICAR (middle). Expression of kinase dead (KD) AMPK rescues polarity in the AICAR treated neuron. Scale bar = 20 μm.
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Figure 1: Figure 1. Schematic illustration depicting the mechanism of AMPK dependent polarity inhibition. (A) Under normal energy conditions AMPK exists in an unphosphorylated/inactive state and PI3K is transported to the neurite tip via a physical association with the kif5 cargo adaptor, KLC. The accumulation of PI3K at a single neurite tip promotes the signaling responsible for axon initiation and growth. (B) Under energy-lacking conditions, AMP binds to AMPK producing a conformational change in the kinase, allowing phospho-activation of AMPK by upstream kinases (AMPKK). AMPK-caused KLC phosphorylation dissociates PI3K, resulting in a loss of PI3K from the neurite tip and an inhibition of neuronal polarization. (C) Cultured hippocampal neurons are transfected with GFP for visualization. Control neuron shows typical single axon (left), which is missing in a neuron treated with AMPK activator AICAR (middle). Expression of kinase dead (KD) AMPK rescues polarity in the AICAR treated neuron. Scale bar = 20 μm.

Mentions: Our recent study has demonstrated that pharmacological activation of AMPK, mimicking energy lacking conditions, during the transition from the symmetric stage 2 to the polarizing stage 3, where the initial signals for axon specification are starting to occur,13 effectively inhibits axon specification and neuronal polarization in both cultured embryonic hippocampal neurons and embryonic cortical brain slices.14 Mechanistically, we show that direct phosphorylation of the kinesin light chain of the motor protein, Kif5, results in a dissociation between the motor complex and its PI3K cargo, thereby preventing PI3K enrichment at the neurite tip, a key mechanism in axon selection and growth9,13 (Fig. 1A and B). Importantly, expression of a kinase dead AMPK mutant (AMPK KD) can rescue polarity in cultured hippocampal neurons and cortical brain slices, regardless of AICAR treatment, indicating that AMPK upregulation, but not its basal activity, regulates neuron polarization (Fig. 1C).14 Consistent with this note, a recent study by Williams et al. has shown that genetic knockout of both AMPK α1/α2 catalytic isoforms in mice had no effect on cortical neurogenesis or polarization.15 To indicate clinical significance, we find that brief ischemia challenge during neuronal development causes phosphorylation of AMPK and inhibition of neuronal polarization in cultured hippocampal neurons.14 Similarly, expression of AMPK KD successfully rescued polarity in ischemia treated neurons, concluding that ischemia induced polarity inhibition is directly mediated by AMPK.


AMPK signaling in neuronal polarization: Putting the brakes on axonal traffic of PI3-Kinase.

Amato S, Man HY - Commun Integr Biol (2012)

Figure 1. Schematic illustration depicting the mechanism of AMPK dependent polarity inhibition. (A) Under normal energy conditions AMPK exists in an unphosphorylated/inactive state and PI3K is transported to the neurite tip via a physical association with the kif5 cargo adaptor, KLC. The accumulation of PI3K at a single neurite tip promotes the signaling responsible for axon initiation and growth. (B) Under energy-lacking conditions, AMP binds to AMPK producing a conformational change in the kinase, allowing phospho-activation of AMPK by upstream kinases (AMPKK). AMPK-caused KLC phosphorylation dissociates PI3K, resulting in a loss of PI3K from the neurite tip and an inhibition of neuronal polarization. (C) Cultured hippocampal neurons are transfected with GFP for visualization. Control neuron shows typical single axon (left), which is missing in a neuron treated with AMPK activator AICAR (middle). Expression of kinase dead (KD) AMPK rescues polarity in the AICAR treated neuron. Scale bar = 20 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3376050&req=5

Figure 1: Figure 1. Schematic illustration depicting the mechanism of AMPK dependent polarity inhibition. (A) Under normal energy conditions AMPK exists in an unphosphorylated/inactive state and PI3K is transported to the neurite tip via a physical association with the kif5 cargo adaptor, KLC. The accumulation of PI3K at a single neurite tip promotes the signaling responsible for axon initiation and growth. (B) Under energy-lacking conditions, AMP binds to AMPK producing a conformational change in the kinase, allowing phospho-activation of AMPK by upstream kinases (AMPKK). AMPK-caused KLC phosphorylation dissociates PI3K, resulting in a loss of PI3K from the neurite tip and an inhibition of neuronal polarization. (C) Cultured hippocampal neurons are transfected with GFP for visualization. Control neuron shows typical single axon (left), which is missing in a neuron treated with AMPK activator AICAR (middle). Expression of kinase dead (KD) AMPK rescues polarity in the AICAR treated neuron. Scale bar = 20 μm.
Mentions: Our recent study has demonstrated that pharmacological activation of AMPK, mimicking energy lacking conditions, during the transition from the symmetric stage 2 to the polarizing stage 3, where the initial signals for axon specification are starting to occur,13 effectively inhibits axon specification and neuronal polarization in both cultured embryonic hippocampal neurons and embryonic cortical brain slices.14 Mechanistically, we show that direct phosphorylation of the kinesin light chain of the motor protein, Kif5, results in a dissociation between the motor complex and its PI3K cargo, thereby preventing PI3K enrichment at the neurite tip, a key mechanism in axon selection and growth9,13 (Fig. 1A and B). Importantly, expression of a kinase dead AMPK mutant (AMPK KD) can rescue polarity in cultured hippocampal neurons and cortical brain slices, regardless of AICAR treatment, indicating that AMPK upregulation, but not its basal activity, regulates neuron polarization (Fig. 1C).14 Consistent with this note, a recent study by Williams et al. has shown that genetic knockout of both AMPK α1/α2 catalytic isoforms in mice had no effect on cortical neurogenesis or polarization.15 To indicate clinical significance, we find that brief ischemia challenge during neuronal development causes phosphorylation of AMPK and inhibition of neuronal polarization in cultured hippocampal neurons.14 Similarly, expression of AMPK KD successfully rescued polarity in ischemia treated neurons, concluding that ischemia induced polarity inhibition is directly mediated by AMPK.

Bottom Line: Our recent work shows that activity of the AMP-activated protein kinase (AMPK), the bio-energy sensor responsible for maintaining cellular energy homeostasis in all eukaryotic cells, plays an important role in the initiation of axonal growth.The mislocation of PI3K, which is normally enriched at the axonal tip for extension and differentiation, results in a lack of neurite specification and neuron polarization.These findings reveal a link between cellular bioenergy homeostasis and neuron morphogenesis, and suggest a novel cellular mechanism underlying the long-term neurological abnormalities as a consequence of bioenergy deficiency during early brain development.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology; Boston University; Boston, MA USA.

ABSTRACT
Neuronal polarization, the process by which neurons form multiple dendrites and an axon from the soma, is the first critical step in the formation and function of neural networks. Polarization begins with the rapid extension of a single neurite to produce an axon of impressive size and complex geometry, while the remaining sister neurites differentiate into dendrites. The extensive biosynthesis required to produce an axon therefore necessitates coordination with cellular energy status to ensure an ample energy supply. Our recent work shows that activity of the AMP-activated protein kinase (AMPK), the bio-energy sensor responsible for maintaining cellular energy homeostasis in all eukaryotic cells, plays an important role in the initiation of axonal growth. AMPK phosphorylates the cargo-binding light chain of the Kif5 motor protein, leading to dissociation of the phosphatidylinositol 3-Kinase (PI3K) from the motor complex. The mislocation of PI3K, which is normally enriched at the axonal tip for extension and differentiation, results in a lack of neurite specification and neuron polarization. These findings reveal a link between cellular bioenergy homeostasis and neuron morphogenesis, and suggest a novel cellular mechanism underlying the long-term neurological abnormalities as a consequence of bioenergy deficiency during early brain development.

No MeSH data available.


Related in: MedlinePlus