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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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Wnd kinase inhibits dendrite growth in C1da neurons expressing ectopic Kn.(A) Wnd overexpression does not alter dendrite morphology in wild-type C1da neurons, but restrains the dendritic overgrowth caused by ectopic Kn in these neurons. Shown are representative dendrites of C1da neurons ddaD (left) and ddaE (right), labeled by Gal42-21/UAS-mCD8::GFP, of the following genotypes: (1) wt; (2) overexpressing Kn by Gal42-21(OE Kn); (3) hiwΔN homozygotes (hiw); (4) overexpressing Wnd by Gal42-21 (OE Wnd); (5) overexpressing Kn and Wnd by Gal42-21 (OE Kn+Wnd); (6) overexpressing Kn and a kinase-dead form of Wnd by Gal42-21(OE Kn+WndKD). Scale bar, 50 ⋯µm. Magnified views of the boxed areas are shown on the right for each genotype. (B) Quantification of total dendrite length (left) and number of dendrite termini (right) of ddaEs of denoted genotypes. (C) Wnd kinase specifically down-regulates the expression of UAS-Kn, but not UAS-RedStinger (a nuclear red fluorescent protein) [66] in a posttranscriptional manner. Representative images of ddaEs labeled with antibodies against Kn (top) and RedStinger (bottom) in “OE Kn+Wnd” and “OE Kn+WndKD” using Gal42-21. Scale bar, 5 µm. (D) Quantification of immunofluorescence intensity of nuclear Kn normalized to that of RedStinger. Two different Gal4 lines, Gal42-21 (left) and Gal421-7 (right), were tested in this experiment.
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pbio-1001572-g006: Wnd kinase inhibits dendrite growth in C1da neurons expressing ectopic Kn.(A) Wnd overexpression does not alter dendrite morphology in wild-type C1da neurons, but restrains the dendritic overgrowth caused by ectopic Kn in these neurons. Shown are representative dendrites of C1da neurons ddaD (left) and ddaE (right), labeled by Gal42-21/UAS-mCD8::GFP, of the following genotypes: (1) wt; (2) overexpressing Kn by Gal42-21(OE Kn); (3) hiwΔN homozygotes (hiw); (4) overexpressing Wnd by Gal42-21 (OE Wnd); (5) overexpressing Kn and Wnd by Gal42-21 (OE Kn+Wnd); (6) overexpressing Kn and a kinase-dead form of Wnd by Gal42-21(OE Kn+WndKD). Scale bar, 50 ⋯µm. Magnified views of the boxed areas are shown on the right for each genotype. (B) Quantification of total dendrite length (left) and number of dendrite termini (right) of ddaEs of denoted genotypes. (C) Wnd kinase specifically down-regulates the expression of UAS-Kn, but not UAS-RedStinger (a nuclear red fluorescent protein) [66] in a posttranscriptional manner. Representative images of ddaEs labeled with antibodies against Kn (top) and RedStinger (bottom) in “OE Kn+Wnd” and “OE Kn+WndKD” using Gal42-21. Scale bar, 5 µm. (D) Quantification of immunofluorescence intensity of nuclear Kn normalized to that of RedStinger. Two different Gal4 lines, Gal42-21 (left) and Gal421-7 (right), were tested in this experiment.

Mentions: We next determined whether Kn expression endows neurons with the ability to respond to dendritic growth control by Wnd. Consistent with previous reports that ectopic expression of Kn in class I da (C1da) neurons leads to excessive dendritic branching and extension [47],[48], the total dendrite length was increased by 55% and the number of dendritic branches was doubled in the C1da neurons overexpressing Kn (OE Kn) compared to wild-type. Such dendritic overgrowth was considerably reduced when Wnd was overexpressed in the same neurons (Figure 6A–B), with the increase in total dendrite length inhibited from 55% to 10%. As a control, a kinase-dead form of Wnd failed to suppress Kn-induced dendritic overgrowth.


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 kinase inhibits dendrite growth in C1da neurons expressing ectopic Kn.(A) Wnd overexpression does not alter dendrite morphology in wild-type C1da neurons, but restrains the dendritic overgrowth caused by ectopic Kn in these neurons. Shown are representative dendrites of C1da neurons ddaD (left) and ddaE (right), labeled by Gal42-21/UAS-mCD8::GFP, of the following genotypes: (1) wt; (2) overexpressing Kn by Gal42-21(OE Kn); (3) hiwΔN homozygotes (hiw); (4) overexpressing Wnd by Gal42-21 (OE Wnd); (5) overexpressing Kn and Wnd by Gal42-21 (OE Kn+Wnd); (6) overexpressing Kn and a kinase-dead form of Wnd by Gal42-21(OE Kn+WndKD). Scale bar, 50 ⋯µm. Magnified views of the boxed areas are shown on the right for each genotype. (B) Quantification of total dendrite length (left) and number of dendrite termini (right) of ddaEs of denoted genotypes. (C) Wnd kinase specifically down-regulates the expression of UAS-Kn, but not UAS-RedStinger (a nuclear red fluorescent protein) [66] in a posttranscriptional manner. Representative images of ddaEs labeled with antibodies against Kn (top) and RedStinger (bottom) in “OE Kn+Wnd” and “OE Kn+WndKD” using Gal42-21. Scale bar, 5 µm. (D) Quantification of immunofluorescence intensity of nuclear Kn normalized to that of RedStinger. Two different Gal4 lines, Gal42-21 (left) and Gal421-7 (right), were tested in this experiment.
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pbio-1001572-g006: Wnd kinase inhibits dendrite growth in C1da neurons expressing ectopic Kn.(A) Wnd overexpression does not alter dendrite morphology in wild-type C1da neurons, but restrains the dendritic overgrowth caused by ectopic Kn in these neurons. Shown are representative dendrites of C1da neurons ddaD (left) and ddaE (right), labeled by Gal42-21/UAS-mCD8::GFP, of the following genotypes: (1) wt; (2) overexpressing Kn by Gal42-21(OE Kn); (3) hiwΔN homozygotes (hiw); (4) overexpressing Wnd by Gal42-21 (OE Wnd); (5) overexpressing Kn and Wnd by Gal42-21 (OE Kn+Wnd); (6) overexpressing Kn and a kinase-dead form of Wnd by Gal42-21(OE Kn+WndKD). Scale bar, 50 ⋯µm. Magnified views of the boxed areas are shown on the right for each genotype. (B) Quantification of total dendrite length (left) and number of dendrite termini (right) of ddaEs of denoted genotypes. (C) Wnd kinase specifically down-regulates the expression of UAS-Kn, but not UAS-RedStinger (a nuclear red fluorescent protein) [66] in a posttranscriptional manner. Representative images of ddaEs labeled with antibodies against Kn (top) and RedStinger (bottom) in “OE Kn+Wnd” and “OE Kn+WndKD” using Gal42-21. Scale bar, 5 µm. (D) Quantification of immunofluorescence intensity of nuclear Kn normalized to that of RedStinger. Two different Gal4 lines, Gal42-21 (left) and Gal421-7 (right), were tested in this experiment.
Mentions: We next determined whether Kn expression endows neurons with the ability to respond to dendritic growth control by Wnd. Consistent with previous reports that ectopic expression of Kn in class I da (C1da) neurons leads to excessive dendritic branching and extension [47],[48], the total dendrite length was increased by 55% and the number of dendritic branches was doubled in the C1da neurons overexpressing Kn (OE Kn) compared to wild-type. Such dendritic overgrowth was considerably reduced when Wnd was overexpressed in the same neurons (Figure 6A–B), with the increase in total dendrite length inhibited from 55% to 10%. As a control, a kinase-dead form of Wnd failed to suppress Kn-induced dendritic overgrowth.

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