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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

Wnd mediates the functions of Hiw on dendritic growth.(A) Loss of wnd blocks dendrite reduction in hiw mutants, and ectopic Wnd restrains dendritic growth. Shown are representative dendrites of ddaC neurons, labeled by ppk-CD4::tdTomato, of the following genotypes: (1) wt; (2) hiwΔN homozygotes (hiw); (3) wnd1/wnd3(wnd); (4) hiwΔN; wnd1/wnd3 double mutants (hiw; wnd); (5) overexpressing Wnd by ppkGal4 (OE Wnd); (6) overexpressing a kinase dead form (K188A) of Wnd by ppkGal4 (OE WndKD). Scale bar, 50 µm. (B) Bar charts showing the quantification of total dendrite length (left) and number of dendrite termini (right). Samples of wt and hiwΔN that are used for statistical analysis are the same as those in Figure 1.
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pbio-1001572-g002: Wnd mediates the functions of Hiw on dendritic growth.(A) Loss of wnd blocks dendrite reduction in hiw mutants, and ectopic Wnd restrains dendritic growth. Shown are representative dendrites of ddaC neurons, labeled by ppk-CD4::tdTomato, of the following genotypes: (1) wt; (2) hiwΔN homozygotes (hiw); (3) wnd1/wnd3(wnd); (4) hiwΔN; wnd1/wnd3 double mutants (hiw; wnd); (5) overexpressing Wnd by ppkGal4 (OE Wnd); (6) overexpressing a kinase dead form (K188A) of Wnd by ppkGal4 (OE WndKD). Scale bar, 50 µm. (B) Bar charts showing the quantification of total dendrite length (left) and number of dendrite termini (right). Samples of wt and hiwΔN that are used for statistical analysis are the same as those in Figure 1.

Mentions: Two parallel downstream pathways are known to mediate axon overgrowth induced by loss of PHR proteins. First, the PHR orthologs in C. elegans (rpm-1) and Drosophila (hiw) suppresses the worm dlk-1 and the fly DLK wallenda (wnd), respectively, to restrain axonal growth in motoneurons [14],[17]. Second, the worm rpm-1 regulates a trafficking pathway that consists of the Rab guanine nucleotide exchange factor (GEF) GLO-4 and the Rab GTPase GLO-1, which restrict axon extension in mechanosensory neurons and synaptogenesis in motoneurons [40]. In order to delineate the mechanism underlying the bimodal control of dendritic and axonal growth by hiw, we tested the involvement of these two pathways in axon and dendrite growth in C4da neurons. While wnd loss-of-function mutations on their own did not alter axonal (Figure S1C–D) or dendritic morphology (Figure 2), they completely suppressed both axonal and dendritic defects caused by hiw mutations (Figure S1C–D and Figure 2). These observations suggest that wnd acts downstream of hiw to promote axonal growth and inhibit dendritic growth.


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)

Wnd mediates the functions of Hiw on dendritic growth.(A) Loss of wnd blocks dendrite reduction in hiw mutants, and ectopic Wnd restrains dendritic growth. Shown are representative dendrites of ddaC neurons, labeled by ppk-CD4::tdTomato, of the following genotypes: (1) wt; (2) hiwΔN homozygotes (hiw); (3) wnd1/wnd3(wnd); (4) hiwΔN; wnd1/wnd3 double mutants (hiw; wnd); (5) overexpressing Wnd by ppkGal4 (OE Wnd); (6) overexpressing a kinase dead form (K188A) of Wnd by ppkGal4 (OE WndKD). Scale bar, 50 µm. (B) Bar charts showing the quantification of total dendrite length (left) and number of dendrite termini (right). Samples of wt and hiwΔN that are used for statistical analysis are the same as those in Figure 1.
© Copyright Policy
Related In: Results  -  Collection

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

pbio-1001572-g002: Wnd mediates the functions of Hiw on dendritic growth.(A) Loss of wnd blocks dendrite reduction in hiw mutants, and ectopic Wnd restrains dendritic growth. Shown are representative dendrites of ddaC neurons, labeled by ppk-CD4::tdTomato, of the following genotypes: (1) wt; (2) hiwΔN homozygotes (hiw); (3) wnd1/wnd3(wnd); (4) hiwΔN; wnd1/wnd3 double mutants (hiw; wnd); (5) overexpressing Wnd by ppkGal4 (OE Wnd); (6) overexpressing a kinase dead form (K188A) of Wnd by ppkGal4 (OE WndKD). Scale bar, 50 µm. (B) Bar charts showing the quantification of total dendrite length (left) and number of dendrite termini (right). Samples of wt and hiwΔN that are used for statistical analysis are the same as those in Figure 1.
Mentions: Two parallel downstream pathways are known to mediate axon overgrowth induced by loss of PHR proteins. First, the PHR orthologs in C. elegans (rpm-1) and Drosophila (hiw) suppresses the worm dlk-1 and the fly DLK wallenda (wnd), respectively, to restrain axonal growth in motoneurons [14],[17]. Second, the worm rpm-1 regulates a trafficking pathway that consists of the Rab guanine nucleotide exchange factor (GEF) GLO-4 and the Rab GTPase GLO-1, which restrict axon extension in mechanosensory neurons and synaptogenesis in motoneurons [40]. In order to delineate the mechanism underlying the bimodal control of dendritic and axonal growth by hiw, we tested the involvement of these two pathways in axon and dendrite growth in C4da neurons. While wnd loss-of-function mutations on their own did not alter axonal (Figure S1C–D) or dendritic morphology (Figure 2), they completely suppressed both axonal and dendritic defects caused by hiw mutations (Figure S1C–D and Figure 2). These observations suggest that wnd acts downstream of hiw to promote axonal growth and inhibit dendritic growth.

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