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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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Kn specifically mediates Hiw regulation of dendritic growth.(A) hiw and kn interact genetically. Shown are representative dendrites of the following genotypes: (1) hiwΔN heterozygote (hiwΔN/+); (2) kn KN4 heterozygote (knKN4/+); (3) hiwΔN and knKN4 trans-heterozygote (hiwΔN/+; knKN4/+). Scale bar, 50 µm. (B) Quantification of total dendrite length of denoted genotypes. wt samples used for statistical analysis are the same as those in Figure 1. (C and C′) Overexpressing Kn partially rescues dendritic defects in hiwΔN mutants. Representative dendrites (C) and tracings (C′) of ddaC MARCM clones of following genotypes: (1) wt; (2) hiwΔN; (3) overexpressing Kn with MARCM (OE Kn); (4) overexpressing Knot in hiwΔN genetic background with MARCM (hiwΔN+OE Kn). Scale bar, 50 µm. (D) Quantification of total dendrite length (left) and number of dendrite termini (right). (E) Overexpressing Kn does not alter axon terminal morphology in hiwΔN mutants. Shown are representative axon terminals of ddaC MARCM clones of the indicated genotypes. Scale bar, 10 µm. (F) Quantification of the length of axon terminals.
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pbio-1001572-g005: Kn specifically mediates Hiw regulation of dendritic growth.(A) hiw and kn interact genetically. Shown are representative dendrites of the following genotypes: (1) hiwΔN heterozygote (hiwΔN/+); (2) kn KN4 heterozygote (knKN4/+); (3) hiwΔN and knKN4 trans-heterozygote (hiwΔN/+; knKN4/+). Scale bar, 50 µm. (B) Quantification of total dendrite length of denoted genotypes. wt samples used for statistical analysis are the same as those in Figure 1. (C and C′) Overexpressing Kn partially rescues dendritic defects in hiwΔN mutants. Representative dendrites (C) and tracings (C′) of ddaC MARCM clones of following genotypes: (1) wt; (2) hiwΔN; (3) overexpressing Kn with MARCM (OE Kn); (4) overexpressing Knot in hiwΔN genetic background with MARCM (hiwΔN+OE Kn). Scale bar, 50 µm. (D) Quantification of total dendrite length (left) and number of dendrite termini (right). (E) Overexpressing Kn does not alter axon terminal morphology in hiwΔN mutants. Shown are representative axon terminals of ddaC MARCM clones of the indicated genotypes. Scale bar, 10 µm. (F) Quantification of the length of axon terminals.

Mentions: It has been demonstrated that loss-of-function mutations of kn cause reduction in dendritic length and branch numbers [46]–[48]. We tested potential genetic interactions between hiw and kn in controlling dendritic growth. C4da dendrites developed normally in both hiwΔN/+ heterozygous and knKN4/+ heterozygous larvae (Figure 5A and B), in which Kn expression and ppk-eGFP levels remained comparable to wild-type (Figure S5D–F). In contrast, the hiwΔN/+; knKN4/+ transheterozygous larvae exhibited dramatically reduced dendritic growth (Figure 5A–B), revealing a strong genetic interaction between hiw and kn.


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)

Kn specifically mediates Hiw regulation of dendritic growth.(A) hiw and kn interact genetically. Shown are representative dendrites of the following genotypes: (1) hiwΔN heterozygote (hiwΔN/+); (2) kn KN4 heterozygote (knKN4/+); (3) hiwΔN and knKN4 trans-heterozygote (hiwΔN/+; knKN4/+). Scale bar, 50 µm. (B) Quantification of total dendrite length of denoted genotypes. wt samples used for statistical analysis are the same as those in Figure 1. (C and C′) Overexpressing Kn partially rescues dendritic defects in hiwΔN mutants. Representative dendrites (C) and tracings (C′) of ddaC MARCM clones of following genotypes: (1) wt; (2) hiwΔN; (3) overexpressing Kn with MARCM (OE Kn); (4) overexpressing Knot in hiwΔN genetic background with MARCM (hiwΔN+OE Kn). Scale bar, 50 µm. (D) Quantification of total dendrite length (left) and number of dendrite termini (right). (E) Overexpressing Kn does not alter axon terminal morphology in hiwΔN mutants. Shown are representative axon terminals of ddaC MARCM clones of the indicated genotypes. Scale bar, 10 µm. (F) Quantification of the length of axon terminals.
© Copyright Policy
Related In: Results  -  Collection

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

pbio-1001572-g005: Kn specifically mediates Hiw regulation of dendritic growth.(A) hiw and kn interact genetically. Shown are representative dendrites of the following genotypes: (1) hiwΔN heterozygote (hiwΔN/+); (2) kn KN4 heterozygote (knKN4/+); (3) hiwΔN and knKN4 trans-heterozygote (hiwΔN/+; knKN4/+). Scale bar, 50 µm. (B) Quantification of total dendrite length of denoted genotypes. wt samples used for statistical analysis are the same as those in Figure 1. (C and C′) Overexpressing Kn partially rescues dendritic defects in hiwΔN mutants. Representative dendrites (C) and tracings (C′) of ddaC MARCM clones of following genotypes: (1) wt; (2) hiwΔN; (3) overexpressing Kn with MARCM (OE Kn); (4) overexpressing Knot in hiwΔN genetic background with MARCM (hiwΔN+OE Kn). Scale bar, 50 µm. (D) Quantification of total dendrite length (left) and number of dendrite termini (right). (E) Overexpressing Kn does not alter axon terminal morphology in hiwΔN mutants. Shown are representative axon terminals of ddaC MARCM clones of the indicated genotypes. Scale bar, 10 µm. (F) Quantification of the length of axon terminals.
Mentions: It has been demonstrated that loss-of-function mutations of kn cause reduction in dendritic length and branch numbers [46]–[48]. We tested potential genetic interactions between hiw and kn in controlling dendritic growth. C4da dendrites developed normally in both hiwΔN/+ heterozygous and knKN4/+ heterozygous larvae (Figure 5A and B), in which Kn expression and ppk-eGFP levels remained comparable to wild-type (Figure S5D–F). In contrast, the hiwΔN/+; knKN4/+ transheterozygous larvae exhibited dramatically reduced dendritic growth (Figure 5A–B), revealing a strong genetic interaction between hiw and kn.

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