Muldal AM et al. (2014), Clonal relationships impact neuronal tuning wit...

XB-ART-49382

Curr Biol 2014 Aug 18;2416:1929-33. doi: 10.1016/j.cub.2014.07.015.

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Clonal relationships impact neuronal tuning within a phylogenetically ancient vertebrate brain structure.

Muldal AM , Lillicrap TP , Richards BA , Akerman CJ .

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Understanding how neurons acquire specific response properties is a major goal in neuroscience. Recent studies in mouse neocortex have shown that "sister neurons" derived from the same cortical progenitor cell have a greater probability of forming synaptic connections with one another and are biased to respond to similar sensory stimuli. However, it is unknown whether such lineage-based rules contribute to functional circuit organization across different species and brain regions. To address this question, we examined the influence of lineage on the response properties of neurons within the optic tectum, a visual brain area found in all vertebrates. Tectal neurons possess well-defined spatial receptive fields (RFs) whose center positions are retinotopically organized. If lineage relationships do not influence the functional properties of tectal neurons, one prediction is that the RF positions of sister neurons should be no more (or less) similar to one another than those of neighboring control neurons. To test this prediction, we developed a protocol to unambiguously identify the daughter neurons derived from single tectal progenitor cells in Xenopus laevis tadpoles. We combined this approach with in vivo two-photon calcium imaging in order to characterize the RF properties of tectal neurons. Our data reveal that the RF centers of sister neurons are significantly more similar than would be expected by chance. Ontogenetic relationships therefore influence the fine-scale topography of the retinotectal map, indicating that lineage relationships may represent a general and evolutionarily conserved principle that contributes to the organization of neural circuits.

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Species referenced: Xenopus laevis
Genes referenced: adm tecta.2

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	Figure 1. Lineage Tracing of Individual Tectal Progenitor Cells(A) Schematic dorsal view of a tadpole’s head (top) illustrating the positions of the two optic tecta (shaded); epifluorescence image (bottom) showing the electroporation of a single tectal progenitor cell with a fluorescently conjugated dextran (red). Region corresponds to dashed box above. ven, ventricle; pz, proliferative zone; ncb, neuronal cell bodies.(B) Two-photon image showing a single tectal progenitor cell captured 2 hr postelectroporation. The scale bar represents 50 μm.(C) Image of a tectal clone consisting of one radial progenitor cell (solid arrowhead) and two daughter neurons (open arrowheads), collected 10 days postelectroporation. The scale bar represents 50 μm.
	Figure 2. Morphology and Laminar Distribution of Tectal Sister Neurons(A) Two-photon image showing a pair of labeled sister neurons (red, open arrowheads) within a tectum loaded with OGB1-AM (cyan). The scale bar represents 50 μm. Boundaries of the nine tectal layers are annotated on the left.(B) Example morphological reconstructions of labeled sister neurons located in different tectal layers (top) and in the same tectal layer (bottom). Dotted white lines denote the positions of the layer boundaries, as determined from the OGB1-AM loading. Scale bars represent 50 μm.(C) Diagram showing the main tectal layers and cell types (left) and laminar fates of labeled sister neurons (right; n = 45 clones). Cell-dense layers are gray; neuropil layers are white. Red circles within each dashed column represent layer positions of daughter neurons generated by a single progenitor cell.
	Figure 3. Two-Photon Calcium Imaging of Sister Neurons and Nearby Nonsister Neurons in the Optic Tectum(A) Experimental setup for in vivo calcium imaging and visual stimulation.(B) Two-photon stack through a region of tectum containing a single clone (red) and loaded with OGB1-AM (cyan). The z axis represents depth relative to the pial surface.(C) Single plane containing two dextran-labeled sister neurons. The scale bar represents 50 μm.(D) Example traces showing visually evoked calcium responses recorded from the neurons labeled in (C). Thin lines denote single trials; thick lines denote the mean response across trials. The corresponding visual stimuli are shown above. Raw spatial RFs and Gaussian fits corresponding to these neurons are also shown (right).(E) Fitted spatial RF maps obtained simultaneously from the two labeled sister neurons (red) and 83 nearby nonsister tectal neurons (cyan) shown in (C), superimposed onto their respective soma positions. The scale bar represents 50 μm.(F) Population data showing that clonally labeled tectal neurons do not differ from nonlabeled neurons in terms of their response magnitude (mean ΔF/F, p = 0.35; maximum ΔF/F, p = 0.31; n = 11 labeled neurons and n = 531 nonlabeled neurons; Mann-Whitney U test), their spatial selectivity (R2 values for Gaussian RF fits, p = 0.34), or the eccentricities of their RFs, as measured by either the euclidean (p = 0.16) or Chebyshev (p = 0.24) distance from the center of the stimulus area to the center of the fitted RF. Plots indicate mean ± SD.
	Figure 4. Sister Neurons in the Optic Tectum Have More Similar Spatial RFs Than Nonsisters(A) Relationship between spatial distance and Δcenter value for all pairs of tectal neurons (∗∗∗p < 0.001, ρ = 0.45, Spearman correlation). Inset illustrates how the Δcenter value was computed for a pair of RFs.(B) Δcenter values for sister and nonsister pairs of tectal neurons (data indicate mean ± SD; n = 13 clonal pairs and n = 72,546 nonclonal pairs from four animals in which a single clone was labeled; ∗∗∗p < 0.001, Mann-Whitney U test).(C) Spatial distances between somata of sister and nonsister pairs (∗∗∗p < 0.001, U test).(D) Schematic showing a pair of sister neurons and its corresponding set of spatially matched nonsister control pairs.(E) Cumulative distribution of Δcenter values for an example pair of sister neurons and its set of matched nonsister control pairs.(F) Pairwise bootstrap test confirms that sister neurons have more similar RF center positions than would be expected, given their spatial proximity within the tectum. Cyan distribution represents a random sample of mean percentile values (Supplemental Experimental Procedures). The mean percentile for sister pairs (red arrow) was significantly smaller than would be expected by chance (∗∗∗p < 0.001, bootstrap test).

References [+] :

Bronner-Fraser, Cell lineage analysis reveals multipotency of some avian neural crest cells. 1988, Pubmed