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


CONCLUSIONS
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.
Su
Cheng-Wen
CW
Institute for Molecular Biology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.|Neuroscience Center Zurich, ETH and University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Tharin
Suzanne
S
Program in Genetics, SUNY at Stony Brook, Stony Brook, NY 11794, USA.|Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.|Current address: Department of Neurosurgery, Brigham and Women's Hospital, Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
Jin
Yishi
Y
Howard Hughes Medical Institute, Department of Molecular, Cellular and Developmental Biology, Sinsheimer Laboratories, University of California, Santa Cruz, CA 95064, USA.
Wightman
Bruce
B
Biology Department, Muhlenberg College, Allentown, PA 18104, USA.
Spector
Mona
M
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Meili
David
D
Institute for Molecular Biology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.|Zoological Institute, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.|Current address: Abteilung für Klinische Chemie und Biochemie, Universitäts-Kinderklinik, Steinwiesstrasse 75, CH-8032 Zürich, Switzerland.
Tsung
Nancy
N
Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.|Current address: Clinigen, Inc., 400 W. Cummings Park #5700, Woburn, MA 01801, USA.
Rhiner
Christa
C
Institute for Molecular Biology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.|Neuroscience Center Zurich, ETH and University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Bourikas
Dimitris
D
Neuroscience Center Zurich, ETH and University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.|Zoological Institute, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Stoeckli
Esther
E
Neuroscience Center Zurich, ETH and University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.|Zoological Institute, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Garriga
Gian
G
Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
Horvitz
H Robert
HR
Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Hengartner
Michael O
MO
Institute for Molecular Biology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.|Neuroscience Center Zurich, ETH and University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000502:physiology; D001692:Biological Transport / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000502:physiology*; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D009479:Neuropeptides / Q000502:physiology*; D013569:Synapses / Q000502:physiology
D029742:Caenorhabditis elegans Proteins; D009479:Neuropeptides; C105447:UNC-76 protein, C elegans; D016547:Kinesins