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The short coiled-coil domain-containing protein UNC-69 cooperates with UNC-76 to regulate axonal outgrowth and normal presynaptic organization in Caenorhabditis elegans.

Su CW, Tharin S, Jin Y, Wightman B, Spector M, Meili D, Tsung N, Rhiner C, Bourikas D, Stoeckli E, Garriga G, Horvitz HR, Hengartner MO - J. Biol. (2006)

Bottom Line: UNC-69 and UNC-76 colocalize as puncta in neuronal processes and cooperate to regulate axon extension and synapse formation.We have identified a novel protein complex, composed of UNC-69 and UNC-76, which promotes axonal growth and normal presynaptic organization in C. elegans.As both proteins are conserved through evolution, we suggest that the mammalian homologs of UNC-69 and UNC-76 (SCOCO and FEZ, respectively) may function similarly.

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Affiliation: Institute for Molecular Biology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. chengwensu@gmail.com

ABSTRACT

Background: The nematode Caenorhabditis elegans has been used extensively to identify the genetic requirements for proper nervous system development and function. Key to this process is the direction of vesicles to the growing axons and dendrites, which is required for growth-cone extension and synapse formation in the developing neurons. The contribution and mechanism of membrane traffic in neuronal development are not fully understood, however.

Results: We show that the C. elegans gene unc-69 is required for axon outgrowth, guidance, fasciculation and normal presynaptic organization. We identify UNC-69 as an evolutionarily conserved 108-amino-acid protein with a short coiled-coil domain. UNC-69 interacts physically with UNC-76, mutations in which produce similar defects to loss of unc-69 function. In addition, a weak reduction-of-function allele, unc-69(ju69), preferentially causes mislocalization of the synaptic vesicle marker synaptobrevin. UNC-69 and UNC-76 colocalize as puncta in neuronal processes and cooperate to regulate axon extension and synapse formation. The chicken UNC-69 homolog is highly expressed in the developing central nervous system, and its inactivation by RNA interference leads to axon guidance defects.

Conclusion: We have identified a novel protein complex, composed of UNC-69 and UNC-76, which promotes axonal growth and normal presynaptic organization in C. elegans. As both proteins are conserved through evolution, we suggest that the mammalian homologs of UNC-69 and UNC-76 (SCOCO and FEZ, respectively) may function similarly.

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UNC-69 is homologous to mammalian SCOCO. (a) Sequence alignment of UNC-69/SCOCO proteins from S. cerevisiae, C. elegans, C. briggsae, mosquito, Drosophila, Fugu, zebrafish, Xenopus, mouse and human. Residues identical in all ten sequences are shaded black; similar residues are shaded gray. The underlined region is predicted in all cases to form a coiled-coil domain. The region boxed in green is acidic, and the region boxed in red is serine/threonine-rich. The bracket indicates the carboxy-terminal basic region. Asterisks mark mutations in unc-69. (b) mRNA of the human unc-69 homolog SCOCO is enriched in fetal brain and is also present in fetal kidney, liver and lung. (c) Expression of human SCOCO rescues the locomotion defect of unc-69 mutant. Movement of the wild type (WT), mutants, and transgenic L4-stage hermaphrodites was scored as complete sine waves per minute. For each genotype n = 10. Error bars represent the standard error of the mean.
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Figure 3: UNC-69 is homologous to mammalian SCOCO. (a) Sequence alignment of UNC-69/SCOCO proteins from S. cerevisiae, C. elegans, C. briggsae, mosquito, Drosophila, Fugu, zebrafish, Xenopus, mouse and human. Residues identical in all ten sequences are shaded black; similar residues are shaded gray. The underlined region is predicted in all cases to form a coiled-coil domain. The region boxed in green is acidic, and the region boxed in red is serine/threonine-rich. The bracket indicates the carboxy-terminal basic region. Asterisks mark mutations in unc-69. (b) mRNA of the human unc-69 homolog SCOCO is enriched in fetal brain and is also present in fetal kidney, liver and lung. (c) Expression of human SCOCO rescues the locomotion defect of unc-69 mutant. Movement of the wild type (WT), mutants, and transgenic L4-stage hermaphrodites was scored as complete sine waves per minute. For each genotype n = 10. Error bars represent the standard error of the mean.

Mentions: We found that UNC-69 is highly conserved through evolution and encodes the C. elegans homolog of mammalian SCOCO (short coiled-coil protein), a protein recently found to interact with dominant-negative ARF-like 1 (ARL1) protein in a yeast two-hybrid screen [20]. The Saccharomyces cerevisiae UNC-69 homolog, Slo1p (SCOCO-like open reading frame protein), has been shown to interact with Arl3p, a homolog of mammalian ARFRP1, another ARF-like protein, which is involved in endoplasmic reticulum-Golgi and post-Golgi transport [21,22]. Uncharacterized UNC-69/SCOCO homologs can also be found in many other animal species (Figure 3a and Additional data file 1).


The short coiled-coil domain-containing protein UNC-69 cooperates with UNC-76 to regulate axonal outgrowth and normal presynaptic organization in Caenorhabditis elegans.

Su CW, Tharin S, Jin Y, Wightman B, Spector M, Meili D, Tsung N, Rhiner C, Bourikas D, Stoeckli E, Garriga G, Horvitz HR, Hengartner MO - J. Biol. (2006)

UNC-69 is homologous to mammalian SCOCO. (a) Sequence alignment of UNC-69/SCOCO proteins from S. cerevisiae, C. elegans, C. briggsae, mosquito, Drosophila, Fugu, zebrafish, Xenopus, mouse and human. Residues identical in all ten sequences are shaded black; similar residues are shaded gray. The underlined region is predicted in all cases to form a coiled-coil domain. The region boxed in green is acidic, and the region boxed in red is serine/threonine-rich. The bracket indicates the carboxy-terminal basic region. Asterisks mark mutations in unc-69. (b) mRNA of the human unc-69 homolog SCOCO is enriched in fetal brain and is also present in fetal kidney, liver and lung. (c) Expression of human SCOCO rescues the locomotion defect of unc-69 mutant. Movement of the wild type (WT), mutants, and transgenic L4-stage hermaphrodites was scored as complete sine waves per minute. For each genotype n = 10. Error bars represent the standard error of the mean.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1561584&req=5

Figure 3: UNC-69 is homologous to mammalian SCOCO. (a) Sequence alignment of UNC-69/SCOCO proteins from S. cerevisiae, C. elegans, C. briggsae, mosquito, Drosophila, Fugu, zebrafish, Xenopus, mouse and human. Residues identical in all ten sequences are shaded black; similar residues are shaded gray. The underlined region is predicted in all cases to form a coiled-coil domain. The region boxed in green is acidic, and the region boxed in red is serine/threonine-rich. The bracket indicates the carboxy-terminal basic region. Asterisks mark mutations in unc-69. (b) mRNA of the human unc-69 homolog SCOCO is enriched in fetal brain and is also present in fetal kidney, liver and lung. (c) Expression of human SCOCO rescues the locomotion defect of unc-69 mutant. Movement of the wild type (WT), mutants, and transgenic L4-stage hermaphrodites was scored as complete sine waves per minute. For each genotype n = 10. Error bars represent the standard error of the mean.
Mentions: We found that UNC-69 is highly conserved through evolution and encodes the C. elegans homolog of mammalian SCOCO (short coiled-coil protein), a protein recently found to interact with dominant-negative ARF-like 1 (ARL1) protein in a yeast two-hybrid screen [20]. The Saccharomyces cerevisiae UNC-69 homolog, Slo1p (SCOCO-like open reading frame protein), has been shown to interact with Arl3p, a homolog of mammalian ARFRP1, another ARF-like protein, which is involved in endoplasmic reticulum-Golgi and post-Golgi transport [21,22]. Uncharacterized UNC-69/SCOCO homologs can also be found in many other animal species (Figure 3a and Additional data file 1).

Bottom Line: UNC-69 and UNC-76 colocalize as puncta in neuronal processes and cooperate to regulate axon extension and synapse formation.We have identified a novel protein complex, composed of UNC-69 and UNC-76, which promotes axonal growth and normal presynaptic organization in C. elegans.As both proteins are conserved through evolution, we suggest that the mammalian homologs of UNC-69 and UNC-76 (SCOCO and FEZ, respectively) may function similarly.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute for Molecular Biology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. chengwensu@gmail.com

ABSTRACT

Background: The nematode Caenorhabditis elegans has been used extensively to identify the genetic requirements for proper nervous system development and function. Key to this process is the direction of vesicles to the growing axons and dendrites, which is required for growth-cone extension and synapse formation in the developing neurons. The contribution and mechanism of membrane traffic in neuronal development are not fully understood, however.

Results: We show that the C. elegans gene unc-69 is required for axon outgrowth, guidance, fasciculation and normal presynaptic organization. We identify UNC-69 as an evolutionarily conserved 108-amino-acid protein with a short coiled-coil domain. UNC-69 interacts physically with UNC-76, mutations in which produce similar defects to loss of unc-69 function. In addition, a weak reduction-of-function allele, unc-69(ju69), preferentially causes mislocalization of the synaptic vesicle marker synaptobrevin. UNC-69 and UNC-76 colocalize as puncta in neuronal processes and cooperate to regulate axon extension and synapse formation. The chicken UNC-69 homolog is highly expressed in the developing central nervous system, and its inactivation by RNA interference leads to axon guidance defects.

Conclusion: We have identified a novel protein complex, composed of UNC-69 and UNC-76, which promotes axonal growth and normal presynaptic organization in C. elegans. As both proteins are conserved through evolution, we suggest that the mammalian homologs of UNC-69 and UNC-76 (SCOCO and FEZ, respectively) may function similarly.

Show MeSH
Related in: MedlinePlus