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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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Transcription factor Fos specifically mediates axonal overgrowth induced by Wnd.(A) Loss of the Drosophila fos, kay, blocks axonal overgrowth caused by Wnd overexpression. Shown are representative axon terminals of ddaC MARCM clones of following genotypes: (1) wt; (2) overexpressing Wnd with MARCM (OE Wnd); (3) kay1; (4) overexpressing Wnd in kay1 genetic background with MARCM (OE Wnd+kay1). Scale bar, 10 µm. (B–B′) kay1 impairs dendritic growth in wt genetic background and exacerbates the dendritic reduction caused by Wnd overexpression. Shown are representative dendrites (B) and tracings (B′) of ddaC MARCM clones of indicated genotypes. Scale bar, 50 µm. (C) Bar charts showing the quantification of axon terminal length (left), total dendrite length (middle), and number of dendrite termini (right).
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pbio-1001572-g003: Transcription factor Fos specifically mediates axonal overgrowth induced by Wnd.(A) Loss of the Drosophila fos, kay, blocks axonal overgrowth caused by Wnd overexpression. Shown are representative axon terminals of ddaC MARCM clones of following genotypes: (1) wt; (2) overexpressing Wnd with MARCM (OE Wnd); (3) kay1; (4) overexpressing Wnd in kay1 genetic background with MARCM (OE Wnd+kay1). Scale bar, 10 µm. (B–B′) kay1 impairs dendritic growth in wt genetic background and exacerbates the dendritic reduction caused by Wnd overexpression. Shown are representative dendrites (B) and tracings (B′) of ddaC MARCM clones of indicated genotypes. Scale bar, 50 µm. (C) Bar charts showing the quantification of axon terminal length (left), total dendrite length (middle), and number of dendrite termini (right).

Mentions: To test the role of Fos with loss-of-function mutants, and to bypass lethality caused by fos mutations kay1[43],[44], we generated kay1 MARCM clones in the presence or absence of a UAS-Wnd transgene that overexpresses Wnd (OE Wnd). kay1 alone did not alter axonal growth (Figure 3A), but completely suppressed the axon overextension caused by Wnd overexpression (Figure 3A and C), which suggests that fos is required for Wnd-induced axonal overgrowth. In contrast to the axonal role of Fos, kay1 did not block the dendritic reduction caused by Wnd overexpression. The total dendritic length of MARCM clones that overexpressed Wnd in the kay1 background (OE Wnd+kay1) was indistinguishable from that of Wnd-overexpressing clones (Figure 3B, B′, and C), and the number of dendrite termini was further reduced from that of Wnd-overexpressing clones. Interestingly, the kay1 mutation alone caused a mild reduction in dendritic length and branch number (Figure 3B, B′, and C). This result suggests that, although Fos does not mediate the dendritic functions of the DLK pathway, it plays a minor role in supporting dendritic growth. Taken together, these results suggest that Wnd acts through Fos to specifically promote axonal 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)

Transcription factor Fos specifically mediates axonal overgrowth induced by Wnd.(A) Loss of the Drosophila fos, kay, blocks axonal overgrowth caused by Wnd overexpression. Shown are representative axon terminals of ddaC MARCM clones of following genotypes: (1) wt; (2) overexpressing Wnd with MARCM (OE Wnd); (3) kay1; (4) overexpressing Wnd in kay1 genetic background with MARCM (OE Wnd+kay1). Scale bar, 10 µm. (B–B′) kay1 impairs dendritic growth in wt genetic background and exacerbates the dendritic reduction caused by Wnd overexpression. Shown are representative dendrites (B) and tracings (B′) of ddaC MARCM clones of indicated genotypes. Scale bar, 50 µm. (C) Bar charts showing the quantification of axon terminal length (left), total dendrite length (middle), and number of dendrite termini (right).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
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pbio-1001572-g003: Transcription factor Fos specifically mediates axonal overgrowth induced by Wnd.(A) Loss of the Drosophila fos, kay, blocks axonal overgrowth caused by Wnd overexpression. Shown are representative axon terminals of ddaC MARCM clones of following genotypes: (1) wt; (2) overexpressing Wnd with MARCM (OE Wnd); (3) kay1; (4) overexpressing Wnd in kay1 genetic background with MARCM (OE Wnd+kay1). Scale bar, 10 µm. (B–B′) kay1 impairs dendritic growth in wt genetic background and exacerbates the dendritic reduction caused by Wnd overexpression. Shown are representative dendrites (B) and tracings (B′) of ddaC MARCM clones of indicated genotypes. Scale bar, 50 µm. (C) Bar charts showing the quantification of axon terminal length (left), total dendrite length (middle), and number of dendrite termini (right).
Mentions: To test the role of Fos with loss-of-function mutants, and to bypass lethality caused by fos mutations kay1[43],[44], we generated kay1 MARCM clones in the presence or absence of a UAS-Wnd transgene that overexpresses Wnd (OE Wnd). kay1 alone did not alter axonal growth (Figure 3A), but completely suppressed the axon overextension caused by Wnd overexpression (Figure 3A and C), which suggests that fos is required for Wnd-induced axonal overgrowth. In contrast to the axonal role of Fos, kay1 did not block the dendritic reduction caused by Wnd overexpression. The total dendritic length of MARCM clones that overexpressed Wnd in the kay1 background (OE Wnd+kay1) was indistinguishable from that of Wnd-overexpressing clones (Figure 3B, B′, and C), and the number of dendrite termini was further reduced from that of Wnd-overexpressing clones. Interestingly, the kay1 mutation alone caused a mild reduction in dendritic length and branch number (Figure 3B, B′, and C). This result suggests that, although Fos does not mediate the dendritic functions of the DLK pathway, it plays a minor role in supporting dendritic growth. Taken together, these results suggest that Wnd acts through Fos to specifically promote axonal 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