Orb2 as modulator of Brat and their role at the neuromuscular junction

Abstract

How synapses are built and dismantled is a central question in neurobiology. A wide range of proteins and processes from gene transcription to protein degradation are involved. Orb2 regulates mRNA translation depending on its monomeric or oligomeric state to modulate nervous system development and memory. Orb2 is expressed in Drosophila larval brain and neuromuscular junction (NMJ), Orb2 knockdown causes a reduction of synapse number and defects in neuronal morphology. Brain tumor (Brat) is an Orb2 target; it is expressed in larval brain related with cell growth and proliferation. Brat downregulation induces an increase in synapse number and abnormal growth of buttons and branches in neurons. In absence of Orb2, Brat is overexpressed suggesting that Orb2 is negatively regulating Brat mRNA translation. Orb2 or Brat control the expression of specific genes related to neuronal function. Orb2 is required for Liprin and Synaptobrevin transcription meanwhile Brat is required for Synaptobrevin and Synaptotagmin transcription. We present here evidences of a novel genetic mechanism to regulate synapse fine tuning during development and propose an equilibrium between Orb2 conformational state and nervous system formation.

Keywords:

• NMJ
• conformational change
• synapse
• gene expression
• central nervous system
• drosophila

Acknowledgments

We thank anonymous reviewers for critiquing the manuscript. We are grateful to J. Knoblich and N. Sonenberg for kindly sending me Brat antibody. Thanks to K. Keleman lab to providing us the Orb2GFP and Orb2^ΔAGFP. We also want to thank the Vienna Drosophila Resource Centre, the Bloomington Drosophila stock Centre and the Developmental Studies Hybridoma Bank for supplying fly stocks and antibodies, and FlyBase for its wealth of information. ES was supported by a FPI grant from the Spanish Ministerio de Economía y competitividad. SC-T holds a Ramon y Cajal contract RyC 2012–11410. Research has been funded by grant BFU2015–65685P from the Spanish Ministry of Economy and Consejo Superior de Investigaciones CientÃficas.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

ES was supported by a FPI grant [grant no. BES-2013-062725] from the Spanish Ministerio de Economía y competitividad. SC-T holds a Ramon y Cajal contract RyC 2012–11410. Research has been funded by grant [grant no. BFU2015–65685P] from the Spanish Ministry of Economy and Consejo Superior de Investigaciones CientÃficas.