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Bimodal control of dendritic and axonal growth by the dual leucine zipper kinase pathway.

Wang X, Kim JH, Bazzi M, Robinson S, Collins CA, Ye B - PLoS Biol. (2013)

Bottom Line: Highwire, an evolutionarily conserved E3 ubiquitin ligase, restrains axonal growth but acts as a positive regulator for dendritic growth in class IV dendritic arborization neurons in the larva.While both the axonal and dendritic functions of highwire require the DLK kinase Wallenda, these two functions diverge through two downstream transcription factors, Fos and Knot, which mediate the axonal and dendritic regulation, respectively.This study not only reveals a previously unknown function of the conserved DLK pathway in controlling dendrite development, but also provides a novel paradigm for understanding how neuronal compartmentalization and the diversity of neuronal morphology are achieved.

View Article: PubMed Central - PubMed

Affiliation: Life Sciences Institute and Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, United States of America.

ABSTRACT
Knowledge of the molecular and genetic mechanisms underlying the separation of dendritic and axonal compartments is not only crucial for understanding the assembly of neural circuits, but also for developing strategies to correct defective dendrites or axons in diseases with subcellular precision. Previous studies have uncovered regulators dedicated to either dendritic or axonal growth. Here we investigate a novel regulatory mechanism that differentially directs dendritic and axonal growth within the same neuron in vivo. We find that the dual leucine zipper kinase (DLK) signaling pathway in Drosophila, which consists of Highwire and Wallenda and controls axonal growth, regeneration, and degeneration, is also involved in dendritic growth in vivo. Highwire, an evolutionarily conserved E3 ubiquitin ligase, restrains axonal growth but acts as a positive regulator for dendritic growth in class IV dendritic arborization neurons in the larva. While both the axonal and dendritic functions of highwire require the DLK kinase Wallenda, these two functions diverge through two downstream transcription factors, Fos and Knot, which mediate the axonal and dendritic regulation, respectively. This study not only reveals a previously unknown function of the conserved DLK pathway in controlling dendrite development, but also provides a novel paradigm for understanding how neuronal compartmentalization and the diversity of neuronal morphology are achieved.

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Related in: MedlinePlus

Hiw differentially regulates dendrite and axon growth in C4da neurons.(A) Dendrites of the C4da neuron ddaC in hiwΔN homozygous mutant larvae are reduced, as compared to wild-type (wt). C4da neurons were labeled by the C4da marker ppk-CD4::tdTomato. Scale bar, 100 µm. (B) Bar charts showing the quantification of total dendrite length (top), number of dendrite termini (bottom) of ddaC in wt, hiwΔN, and hiwND8 larvae. Sample numbers are shown in the bars of the bar charts throughout this article. (C–D) hiw mutant MARCM clones exhibit impaired dendritic growth and overgrowth of axon terminals. (C) Representative dendrites of wt and hiwΔN mutant ddaC neurons. Scale bar, 50 µm. (D) Representative axon terminals of a single wt ddaC and a single hiwΔN mutant ddaC. The axon terminals of wild-type ddaC clones (green) extend within one segment length of the C4da neuropil (magenta) labeled by ppk-CD4::tdTomato. The axon terminals of hiwΔN mutant clones (green) expand over multiple segment lengths of the C4da neuropil (magenta). Scale bar, 10 µm. (E) Quantification of total dendrite length (left) and number of dendrite termini (right) of wt and hiwΔN MARCM clones. (F) Quantification of axon terminal length of wt and hiwΔN MARCM clones.
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pbio-1001572-g001: Hiw differentially regulates dendrite and axon growth in C4da neurons.(A) Dendrites of the C4da neuron ddaC in hiwΔN homozygous mutant larvae are reduced, as compared to wild-type (wt). C4da neurons were labeled by the C4da marker ppk-CD4::tdTomato. Scale bar, 100 µm. (B) Bar charts showing the quantification of total dendrite length (top), number of dendrite termini (bottom) of ddaC in wt, hiwΔN, and hiwND8 larvae. Sample numbers are shown in the bars of the bar charts throughout this article. (C–D) hiw mutant MARCM clones exhibit impaired dendritic growth and overgrowth of axon terminals. (C) Representative dendrites of wt and hiwΔN mutant ddaC neurons. Scale bar, 50 µm. (D) Representative axon terminals of a single wt ddaC and a single hiwΔN mutant ddaC. The axon terminals of wild-type ddaC clones (green) extend within one segment length of the C4da neuropil (magenta) labeled by ppk-CD4::tdTomato. The axon terminals of hiwΔN mutant clones (green) expand over multiple segment lengths of the C4da neuropil (magenta). Scale bar, 10 µm. (E) Quantification of total dendrite length (left) and number of dendrite termini (right) of wt and hiwΔN MARCM clones. (F) Quantification of axon terminal length of wt and hiwΔN MARCM clones.

Mentions: To examine the role of hiw in dendritic development, we labeled the C4da neurons in hiw mutant larvae using a C4da-specific marker, ppk-CD4::tdTomato[34],[36]. We found that dendritic growth was dramatically reduced in the allele hiwΔN and, to a lesser extent, in the hypomorphic hiwND8 mutants (Figure 1A and B). Both total length and number of termini of dendrites were significantly reduced in hiwΔN and hiwND8 mutants (Figure 1B).


Bimodal control of dendritic and axonal growth by the dual leucine zipper kinase pathway.

Wang X, Kim JH, Bazzi M, Robinson S, Collins CA, Ye B - PLoS Biol. (2013)

Hiw differentially regulates dendrite and axon growth in C4da neurons.(A) Dendrites of the C4da neuron ddaC in hiwΔN homozygous mutant larvae are reduced, as compared to wild-type (wt). C4da neurons were labeled by the C4da marker ppk-CD4::tdTomato. Scale bar, 100 µm. (B) Bar charts showing the quantification of total dendrite length (top), number of dendrite termini (bottom) of ddaC in wt, hiwΔN, and hiwND8 larvae. Sample numbers are shown in the bars of the bar charts throughout this article. (C–D) hiw mutant MARCM clones exhibit impaired dendritic growth and overgrowth of axon terminals. (C) Representative dendrites of wt and hiwΔN mutant ddaC neurons. Scale bar, 50 µm. (D) Representative axon terminals of a single wt ddaC and a single hiwΔN mutant ddaC. The axon terminals of wild-type ddaC clones (green) extend within one segment length of the C4da neuropil (magenta) labeled by ppk-CD4::tdTomato. The axon terminals of hiwΔN mutant clones (green) expand over multiple segment lengths of the C4da neuropil (magenta). Scale bar, 10 µm. (E) Quantification of total dendrite length (left) and number of dendrite termini (right) of wt and hiwΔN MARCM clones. (F) Quantification of axon terminal length of wt and hiwΔN MARCM clones.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3672216&req=5

pbio-1001572-g001: Hiw differentially regulates dendrite and axon growth in C4da neurons.(A) Dendrites of the C4da neuron ddaC in hiwΔN homozygous mutant larvae are reduced, as compared to wild-type (wt). C4da neurons were labeled by the C4da marker ppk-CD4::tdTomato. Scale bar, 100 µm. (B) Bar charts showing the quantification of total dendrite length (top), number of dendrite termini (bottom) of ddaC in wt, hiwΔN, and hiwND8 larvae. Sample numbers are shown in the bars of the bar charts throughout this article. (C–D) hiw mutant MARCM clones exhibit impaired dendritic growth and overgrowth of axon terminals. (C) Representative dendrites of wt and hiwΔN mutant ddaC neurons. Scale bar, 50 µm. (D) Representative axon terminals of a single wt ddaC and a single hiwΔN mutant ddaC. The axon terminals of wild-type ddaC clones (green) extend within one segment length of the C4da neuropil (magenta) labeled by ppk-CD4::tdTomato. The axon terminals of hiwΔN mutant clones (green) expand over multiple segment lengths of the C4da neuropil (magenta). Scale bar, 10 µm. (E) Quantification of total dendrite length (left) and number of dendrite termini (right) of wt and hiwΔN MARCM clones. (F) Quantification of axon terminal length of wt and hiwΔN MARCM clones.
Mentions: To examine the role of hiw in dendritic development, we labeled the C4da neurons in hiw mutant larvae using a C4da-specific marker, ppk-CD4::tdTomato[34],[36]. We found that dendritic growth was dramatically reduced in the allele hiwΔN and, to a lesser extent, in the hypomorphic hiwND8 mutants (Figure 1A and B). Both total length and number of termini of dendrites were significantly reduced in hiwΔN and hiwND8 mutants (Figure 1B).

Bottom Line: Highwire, an evolutionarily conserved E3 ubiquitin ligase, restrains axonal growth but acts as a positive regulator for dendritic growth in class IV dendritic arborization neurons in the larva.While both the axonal and dendritic functions of highwire require the DLK kinase Wallenda, these two functions diverge through two downstream transcription factors, Fos and Knot, which mediate the axonal and dendritic regulation, respectively.This study not only reveals a previously unknown function of the conserved DLK pathway in controlling dendrite development, but also provides a novel paradigm for understanding how neuronal compartmentalization and the diversity of neuronal morphology are achieved.

View Article: PubMed Central - PubMed

Affiliation: Life Sciences Institute and Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, United States of America.

ABSTRACT
Knowledge of the molecular and genetic mechanisms underlying the separation of dendritic and axonal compartments is not only crucial for understanding the assembly of neural circuits, but also for developing strategies to correct defective dendrites or axons in diseases with subcellular precision. Previous studies have uncovered regulators dedicated to either dendritic or axonal growth. Here we investigate a novel regulatory mechanism that differentially directs dendritic and axonal growth within the same neuron in vivo. We find that the dual leucine zipper kinase (DLK) signaling pathway in Drosophila, which consists of Highwire and Wallenda and controls axonal growth, regeneration, and degeneration, is also involved in dendritic growth in vivo. Highwire, an evolutionarily conserved E3 ubiquitin ligase, restrains axonal growth but acts as a positive regulator for dendritic growth in class IV dendritic arborization neurons in the larva. While both the axonal and dendritic functions of highwire require the DLK kinase Wallenda, these two functions diverge through two downstream transcription factors, Fos and Knot, which mediate the axonal and dendritic regulation, respectively. This study not only reveals a previously unknown function of the conserved DLK pathway in controlling dendrite development, but also provides a novel paradigm for understanding how neuronal compartmentalization and the diversity of neuronal morphology are achieved.

Show MeSH
Related in: MedlinePlus