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The Journal of Neuroscience, January 14, 2009, 29(2):517-528; doi:10.1523/JNEUROSCI.3848-08.2009

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Development/Plasticity/Repair
Unc-51 Controls Active Zone Density and Protein Composition by Downregulating ERK Signaling

Yogesh P. Wairkar,¹ Hirofumi Toda,^2,3 Hiroaki Mochizuki,³ Katsuo Furukubo-Tokunaga,³ Toshifumi Tomoda,² and Aaron DiAntonio¹

¹Department of Developmental Biology, Washington University in St. Louis, St. Louis, Missouri 63110, ²Division of Neurosciences, Beckman Research Institute of the City of Hope, Duarte, California 91010, and ³Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba 305-8572, Japan

Correspondence should be addressed to Aaron DiAntonio, Department of Developmental Biology, Washington University in St. Louis, 660 South Euclid Avenue, Campus Box #8103, St. Louis, MO 63110. Email: diantonio{at}wustl.edu

Efficient synaptic transmission requires the apposition of neurotransmitter release sites opposite clusters of postsynaptic neurotransmitter receptors. Transmitter is released at active zones, which are composed of a large complex of proteins necessary for synaptic development and function. Many active zone proteins have been identified, but little is known of the mechanisms that ensure that each active zone receives the proper complement of proteins. Here we use a genetic analysis in Drosophila to demonstrate that the serine threonine kinase Unc-51 acts in the presynaptic motoneuron to regulate the localization of the active zone protein Bruchpilot opposite to glutamate receptors at each synapse. In the absence of Unc-51, many glutamate receptor clusters are unapposed to Bruchpilot, and ultrastructural analysis demonstrates that fewer active zones contain dense body T-bars. In addition to the presence of these aberrant synapses, there is also a decrease in the density of all synapses. This decrease in synaptic density and abnormal active zone composition is associated with impaired evoked transmitter release. Mechanistically, Unc-51 inhibits the activity of the MAP kinase ERK to promote synaptic development. In the unc-51 mutant, increased ERK activity leads to the decrease in synaptic density and the absence of Bruchpilot from many synapses. Hence, activated ERK negatively regulates synapse formation, resulting in either the absence of active zones or the formation of active zones without their proper complement of proteins. The Unc-51-dependent inhibition of ERK activity provides a potential mechanism for synapse-specific control of active zone protein composition and release probability.

Key words: autophagy; NMJ; synapse; Drosophila; ATG; active zones; glutamate receptors

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Received Aug. 13, 2008; revised Dec. 4, 2008; accepted Dec. 9, 2008.

Correspondence should be addressed to Aaron DiAntonio, Department of Developmental Biology, Washington University in St. Louis, 660 South Euclid Avenue, Campus Box #8103, St. Louis, MO 63110. Email: diantonio{at}wustl.edu

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				W. Shen and B. Ganetzky Autophagy promotes synapse development in Drosophila J. Cell Biol., October 5, 2009; 187(1): 71 - 79. [Abstract] [Full Text] [PDF]

				N. M. Viquez, P. Fuger, V. Valakh, R. W. Daniels, T. M. Rasse, and A. DiAntonio PP2A and GSK-3{beta} Act Antagonistically to Regulate Active Zone Development J. Neurosci., September 16, 2009; 29(37): 11484 - 11494. [Abstract] [Full Text] [PDF]

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