Serial Synapse Formation through Filopodial Competition for Synaptic Seeding Factors

Özel, Mehmet Neset; Kulkarni, Abhishek; Hasan, Amr; Brummer, Josephine; Moldenhauer, Marian; Daumann, Ilsa-Maria; Wolfenberg, Heike; Dercksen, Vincent J.; Kiral, Ferdi Rıdvan; Weiser, Martin; Prohaska, Steffen; Kleist, Max von; Hiesinger, P. Robin

doi:10.1016/j.devcel.2019.06.014

Cited by 42 publications

(67 citation statements)

References 60 publications

(91 reference statements)

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“…Considering that the R7 growth cone begins to form presynaptic terminals in layer M6 65 hr after puparium formation (APF) (Chen et al, ), it would be interesting to determine whether extension begins before or after this stage. Recent study from Hiesinger group suggested that the synapse formation stabilizes the extended filopodia through live imaging experiment (Özel et al, ). If that is the case, it is possible that the major cause of the ectopic synapse formation in the klg mutant is due to the enhancement of the filopodia dynamics.…”

Section: Discussionmentioning

confidence: 99%

Cell surface molecule, Klingon, mediates the refinement of synaptic specificity in the Drosophila visual system

et al. 2019

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In the Drosophila brain, neurons form genetically specified synaptic connections with defined neuronal targets. It is proposed that each central nervous system neuron expresses specific cell surface proteins, which act as identification tags. Through an RNAi screen of cell surface molecules in the Drosophila visual system, we found that the cell adhesion molecule Klingon (Klg) plays an important role in repressing the ectopic formation of extended axons, preventing the formation of excessive synapses. Cell‐specific manipulation of klg showed that Klg is required in both photoreceptors and the glia, suggesting that the balanced homophilic interaction between photoreceptor axons and the glia is required for normal synapse formation. Previous studies suggested that Klg binds to cDIP and our genetic analyses indicate that cDIP is required in glia for ectopic synaptic repression. These data suggest that Klg play a critical role together with cDIP in refining synaptic specificity and preventing unnecessary connections in the brain.

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Section: Discussionmentioning

confidence: 99%

Cell surface molecule, Klingon, mediates the refinement of synaptic specificity in the Drosophila visual system

et al. 2019

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“…To assess whether the alterations in neurotransmission and vision were due to altered numbers of synapses, we generated sparse clones of photoreceptors R1-R6, and R7 expressing the active zone marker GFP-Brp short . This marker specifically localizes to presynaptic active zones without affecting synaptic development or function and is suitable for live imaging 14,33 . Loss of autophagy resulted in a 25%-80% increase in synapse numbers, while increased autophagy in rescued atg6 mutant photoreceptors reversed this effect and significantly reduced synapse numbers (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…the speed or stability of filopodial interactions, is almost completely unknown for dense brain regions in any organism. Our limited understanding of the dynamics of synaptogenic encounters reflects the difficulty to observe, live and in vivo , synapse formation at the level of filopodial dynamics in intact, normally developing brains 13,14 .…”

Section: Introductionmentioning

confidence: 99%

“…Fly photoreceptors (R cells) are the primary retinal output neurons that relay visual information with highly stereotypic synaptic connections in dense brain regions, namely the lamina and medulla neuropils of the optic lobe 15–17 . Intact fly brains can develop in culture, enabling live imaging at the high spatiotemporal resolution necessary to measure photoreceptor axon filopodial dynamics and synapse formation throughout the entire developmental period of circuit assembly 13,14,18 . Axonal filopodia inside the developing brain stabilize to form synapses through the accumulation of synaptic building material, but how limiting amounts of building material in filopodia are regulated is unknown 14 .…”

Section: Introductionmentioning

confidence: 99%

“…Intact fly brains can develop in culture, enabling live imaging at the high spatiotemporal resolution necessary to measure photoreceptor axon filopodial dynamics and synapse formation throughout the entire developmental period of circuit assembly 13,14,18 . Axonal filopodia inside the developing brain stabilize to form synapses through the accumulation of synaptic building material, but how limiting amounts of building material in filopodia are regulated is unknown 14 .…”

Section: Introductionmentioning

confidence: 99%

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Autophagy-dependent filopodial kinetics restrict synaptic partner choice during Drosophila brain wiring

Kiral

Linneweber

Georgiev

et al. 2019

Preprint

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11Brain wiring is remarkably precise, yet most neurons readily form synapses with 12 incorrect partners when given the opportunity. Dynamic axon-dendritic positioning can 13 restrict synaptogenic encounters, but the spatiotemporal interaction kinetics and their 14 regulation remain essentially unknown inside developing brains. Here we show that the 15 kinetics of axonal filopodia restrict synapse formation and partner choice for neurons that are 16 not otherwise prevented from making incorrect synapses. Using 4D imaging in developing 17 Drosophila brains, we show that filopodial kinetics are regulated by autophagy, a prevalent 18 degradation mechanism whose role in brain development remains poorly understood. With 19 surprising specificity, autophagosomes form in synaptogenic filopodia, followed by filopodial 20 collapse. Altered autophagic degradation of synaptic building material quantitatively 21 regulates synapse formation as shown by computational modeling and genetic experiments. 22Increased filopodial stability enables incorrect synaptic partnerships. Hence, filopodial 23 autophagy restricts inappropriate partner choice through a process of kinetic exclusion that 24 critically contributes to wiring specificity. 25 26 27 30 most, if not all, neurons have the ability to form synapses with incorrect partners, including 31 themselves 6,7 . During neural circuit development, spatiotemporal patterning restricts when 32 and where neurons 'see each other' [8][9][10] . Positional effects can thereby prevent incorrect 33 partnerships, even when neurons are not otherwise prevented from forming synapses 7,11,12 . 34 When and where neurons interact with each other to form synapses is a fundamentally 35 dynamic process. Yet, the roles of neuronal interaction dynamics, e.g. the speed or stability 36 of filopodial interactions, is almost completely unknown for dense brain regions in any 37 organism. Our limited understanding of the dynamics of synaptogenic encounters reflects the 38 2 difficulty to observe, live and in vivo, synapse formation at the level of filopodial dynamics in 39 intact, normally developing brains 13,14 . 40 Fly photoreceptors (R cells) are the primary retinal output neurons that relay visual 41 information with highly stereotypic synaptic connections in dense brain regions, namely the 42 lamina and medulla neuropils of the optic lobe [15][16][17] . Intact fly brains can develop in culture, 43 enabling live imaging at the high spatiotemporal resolution necessary to measure 44 photoreceptor axon filopodial dynamics and synapse formation throughout the entire 45 developmental period of circuit assembly 13,14,18 . Axonal filopodia inside the developing brain 46 stabilize to form synapses through the accumulation of synaptic building material, but how 47 limiting amounts of building material in filopodia are regulated is unknown 14 . 48Macroautophagy (autophagy hereafter) is a ubiquitous endomembrane degradation 49 mechanism implicated in neuronal maintenance and function 19 . Neuronal autoph...

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Brain wiring with composite instructions

Hiesinger

2020

BioEssays

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The quest for molecular mechanisms that guide axons or specify synaptic contacts has largely focused on molecules that intuitively relate to the idea of an "instruction." By contrast, "permissive" factors are traditionally considered background machinery without contribution to the information content of a molecularly executed instruction. In this essay, I recast this dichotomy as a continuum from permissive to instructive actions of single factors that provide relative contributions to a necessarily collaborative effort. Individual molecules or other factors do not constitute absolute instructions by themselves; they provide necessary context for each other, thereby creating a composite that defines the overall instruction. The idea of composite instructions leads to two main conclusions: first, a composite of many seemingly permissive factors can define a specific instruction even in the absence of a single dominant contributor; second, individual factors are not necessarily related intuitively to the overall instruction or phenotypic outcome.

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Serial Synapse Formation through Filopodial Competition for Synaptic Seeding Factors

Abstract: Highlights d Stochastic filopodia dynamics are required for robust synapse formation in fly brains d Only 1-2 filopodia at a time contain synaptic seeding factors and are synaptogenic d 4D tracking and computational modeling support a serial synapse formation model

Cited by 42 publications

References 60 publications

Cell surface molecule, Klingon, mediates the refinement of synaptic specificity in the Drosophila visual system

Cell surface molecule, Klingon, mediates the refinement of synaptic specificity in the Drosophila visual system

Autophagy-dependent filopodial kinetics restrict synaptic partner choice during Drosophila brain wiring

Brain wiring with composite instructions

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