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Transcription factor control of dendrite targeting via combinatorial cell-surface codes

By Qijing Xie, Jiefu Li, Hongjie Li, Namrata D Udeshi, Tanya Svinkina, Sayeh Kohani, Ricardo Guajardo, D R Mani, Chuanyun Xu, Tongchao Li, Shuo Han, Wei Wei, S. Andrew Shuster, David J. Luginbuhl, Alice Y. Ting, Steven A Carr, Liqun Luo

Posted 04 Nov 2021
bioRxiv DOI: 10.1101/2021.11.03.467130

Transcription factors are central commanders specifying cell fate, morphology, and physiology while cell-surface proteins execute these commands through interaction with cellular environment. In developing neurons, it is presumed that transcription factors control wiring specificity through regulation of cell-surface protein expression. However, the number and identity of cell-surface protein(s) a transcription factor regulates remain largely unclear1,2. Also unknown is whether a transcription factor regulates the same or different cell-surface proteins in different neuron types to specify their connectivity. Here we use a lineage-defining transcription factor, Acj6 (ref. 3), to investigate how it controls precise dendrite targeting of Drosophila olfactory projection neurons (PNs). Quantitative cell-surface proteomic profiling of wild-type and acj6 mutant PNs in intact developing brains and a proteome-informed genetic screen identified PN surface proteins that execute Acj6-regulated wiring decisions. These include canonical cell adhesion proteins and proteins previously not associated with wiring, such as the mechanosensitive ion channel Piezo-whose channel activity is dispensable for its wiring function. Comprehensive genetic analyses revealed that Acj6 employs unique sets of cell-surface proteins in different PN types for dendrite targeting. Combinatorial expression of Acj6 wiring executors rescued acj6 mutant phenotypes with higher efficacy and breadth than expression of individual executors. Thus, a key transcription factor controls wiring specificity of different neuron types by specifying distinct combinatorial expression of cell-surface executors.

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