. .. I-als,

, The neuromuscular junction (NMJ)

. .. Ii-dynactin1, 1-The different domains of dynactin1, 9 II.2-Disassembly of the dynactin complex from dynein

, 16 II.6-Alternative splicing: p135 versus p150

.. .. Results, 28 I-Morphological phenotype of the mikre oko (mok) m632-/-embryos

. .. , 33 VI-Quantitative RT-PCR profile of 6dpf mok m632-/-embryos, IV-Axonal morphology at 48hpf and 6dpf

. .. Dctn1, 36 VII.1-Axonal morphology at 6dpf, VII-Rescue of the axonal morphology phenotype with human

.. .. Ix-putative, 41 X-Spontaneous activity of the CaPs in the spinal cord at 4dpf

, 43 XII-Neuromuscular junction paired-recordings at 6dpf, XI-Neuromuscular junction mEPC at 6dpf

.. .. Xiii-axonal-transport, 46 XIII.1-Choice of cargo and method of expression

, 3-Cargo behavior and run metrics at 48hpf

.. .. Xiv-trophic-signaling-involvement,

.. .. Xv-microtubule, 64 xi XVII-Synaptic microtubule capture at 48hpf and 6dpf

.. .. Xix-controls, 69 XIX.2-Other dynein/dynactin mutant and DN-dynactin1 axonal morphology

.. .. Discussion,

P. .. Conclusion, , vol.87

. Materials and . .. Methods,

I. and .. .. ,

. .. Ii-microinjections,

.. .. Iv-molecular-cloning,

V. and .. .. ,

.. .. Vi-microscopy,

. .. Viii-quantitative-rt-pcr,

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. Kwan, we amplified a truncated fragment of ntrk3A from wild-type zebrafish cDNA (3 dpf) and fused it to the eGFP open reading frame. Primers used are listed in Supplementary file 2. After digestion and insertion into the pME-MCS vector with HindIII and NotI we performed a Gateway reaction using p5E-10UAS, pMEntrk3AdNeGFP, p3E-pA and pDest-Tol2; cmlc2:eGFP to generate p10UAS:ntrk3adNeGFP-pA-Tol2; cmcl2:eGFP. To create a pIsl2b:eGFPCaax construct, we performed a Gateway reaction using p5E-Isl2b, pME-eGFPCaax, 2007.

(. Warren, 1999) and the pax2.1 probe was synthesized using the complete pax2.1 cDNA, 1991.

. Emd-millipore, M. A. Billerica, and . Mab1572, :5000). The following secondary antibodies were used in the course of this study: anti-mouse-Alexa635, ThermoFisher Scientific, A31574, 1:250), anti-rabbitAlexa546 (ThermoFisher Scientific, A11081, 1:250), anti-chicken-Alexa488 (ThermoFisher Scientific, A11039, 1:250), anti-Rabbit IgG, vol.1, pp.1-18385, 2000.

. Muto, Optokinetic response The behavioral test for the optokinetic response was performed as described previously, 2005.

, Single cell labeling and filopodia analysis The morphology of single RGCs was analyzed using the Tg(BGUG), p.5

, To quantify filopodia dynamics, imaging was performed for 10 min at a rate of 1 frame/2 min. All branches not extending within this imaging period were assigned as stable branches and used for quantification of branch number and length. All branches extended or retracted within this imaging period were defined as filopodia. Single cell labeling to analyze synapse and mitochondria distribution was achieved by injection of 1 nl of naked plasmid DNA (25 ng/?l) into 1 cell stage embryos of the Tg, +/? transgenic line and single cells were imaged over consecutive days

, To generate single RGCs expressing the dominant negative ntrk3a receptor, we injected 1 nl of naked p10UAS:ntrk3aDN-eGFP-pA-Tol2;cmcl2:eGFP plasmid DNA into 1 cell stage embryos of the Tg(Pou3f4:Gal4), nacre+/? transgenic line. To generate single eGFP expressing RGCs growing into a ntf3 overexpressing tectum, we performed injections of 0.1 ng/?l pIsl2b:eGFPCaax plasmid DNA, 15 ng/?l p10UAS:ntf3-E2A-tagRFP-pA-tol2, cmcl2:eGFP plasmid DNA and 50 ng/?l Tol2 transposase mRNA into 1 cell stage embryos of the Tg(gSA2AzGFF49A) (Muto et al., 2013) transgenic line, vol.2

, ) diluted in egg water and embedded in 1% low melting-point agarose in glassbottom cell tissue culture dish (Fluorodish, World Precision Instruments, Confocal microscopy Imaging was performed on a Roper confocal spinning disk head mounted on a Zeiss upright microscope, and acquisitions were done with a CoolSNAP HQ2 CDD camera (Photometrics, USA) through the MetaMorph software (Molecular Devices

, 421462-9900) for z-stack images of the whole tectum and at 63× magnification (W PL APO VIS-IR; 421480-9900) for single plane time-lapse imaging of linear axonal segments. Images were assembled and analyzed in ImageJ (NIH). Z-stack images were manual edited to remove skin autofluorescence

. Moughamian, 2013) based on the speed of transport in the tectum and set at 5 s intervals for 15 min (SypGFP) and 20 min (mitoGFP) total duration. Time-lapse images were assembled and analyzed in ImageJ to determine the percentage of moving vs stable particles, as well as distribution/density and size of the organelles. Kymograms were extracted for each linear segment using the kymogram tool, Time-lapse imaging, kymogram production and analysis Time-lapse parameters were determined similar to previous studies, 2013.

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. .. , 55 Figure 26: Axonal transport metrics for recycling endosomes at 48hpf. A) Directionality ratio chart for late recycling movement, where stable vesicles were labeled as "immobile" (black), non-mobile but unstable vesicles were labeled as "oscillating" (grey), retrogradedirected mobile vesicles as "retrograde" (magenta) and anterograde-directed mobile vesicles as "anterograde" (cyan). B) Area flux was determined for both direction (number of moving vesicles per minute, per 20 ?m) and density (number of vesicles per 20 ?m) was measured. Individual runs are defined as unbroken linear segments of movement, and were used to extract metrics for the C) retrograde direction and the D) anterograde direction for average run speed (?m/s), average run length (?m) and average run duration (s). All data averaged by kymogram and presented as average +/-SEM. (n=18,19), All data averaged by kymogram and presented as average +/-SEM. (n=27,30), vol.27

, 58 Figure 28: Filopodia dynamics at 24hpf, 48hpf, 72hpf and 4dpf. Filipodial dynamics were acquired by timelapse imaging, where a confocal z-stack of the axonal arbor was acquired every two minutes for a total of ten minutes (2/10minutes). A)The z-stack projections were then used to compare the growth and retraction of filopodia between the 6 timepoints, the sum of which is reported here as total unstable filopodia, A) Representative kymograms used for analysis, where retrograde-directed mobile vesicle runs (magenta) and anterograde-directed mobile vesicles runs (cyan) are labeled