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J Neurosci
2008 Jan 02;281:100-5. doi: 10.1523/JNEUROSCI.4490-07.2008.
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NF-protocadherin and TAF1 regulate retinal axon initiation and elongation in vivo.
Piper M
,
Dwivedy A
,
Leung L
,
Bradley RS
,
Holt CE
.
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NF-protocadherin (NFPC)-mediated cell-cell adhesion plays a critical role in vertebrate neural tube formation. NFPC is also expressed during the period of axon tract formation, but little is known about its function in axonogenesis. Here we have tested the role of NFPC and its cytosolic cofactor template-activating factor 1 (TAF1) in the emergence of the Xenopus retinotectal projection. NFPC is expressed in the developing retina and optic pathway and is abundant in growing retinal axons. Inhibition of NFPC function in developing retinal ganglion cells (RGCs) severely reduces axon initiation and elongation and suppresses dendrite genesis. Furthermore, an identical phenotype occurs when TAF1 function is blocked. These data provide evidence that NFPC regulates axon initiation and elongation and indicate a conserved role for TAF1, a transcriptional regulator, as a downstream cytosolic effector of NFPC in RGCs.
Figure 1.
Retinal expression of NFPC and TAF1. A, Transverse section of a stage 40 retina, showing NFPC mRNA expression in the plexiform layers (arrowheads), ONH (double arrowhead), and RGC layer (arrow). B, Whole-mount ISH of an isolated stage 40 brain. NFPC mRNA delineates the optic tract (arrowhead) and is seen in the forebrain (arrow), tectum (double arrowhead), and hypothalamus (open arrowhead). A, Anterior; D, dorsal; P, posterior; V, ventral. C, Reverse side of the brain shown in B, in which retinal axons have been HRP filled, so they appear brown. The HRP signal is coincident with NFPC mRNA in the optic tract. D, At stage 40, the lens, plexiform layers (arrowheads), RGCs (arrow), and ONH (double arrowhead) express NFPC protein. E, Cultured RGCneurite from a stage 24 retinal explant expressing NFPC on the neurite shaft and growth cone. F, Retinal TAF1 mRNA expression is found in the RGC layer (arrow), ONH (double arrowhead), and the plexiform layers (arrowheads) at stage 40. G, Cultured stage 24 retinal neurite expressing TAF1. IF, Immunofluorescence. Dotted lines in E and G delineate the edge of the growth cone. Scale bar: B, C, 400 μm; A, D, F, 250 μm; E, G, 5 μm.
Figure 2.
NFΔE-expressing cells differentiate into multiple retinal cell types. A–H, Transverse sections of stage 40 retinas immunolabeled with an anti-myc antibody to identify NFΔE-expressing cells. NFΔE-expressing cells can differentiate into photoreceptors (A, ph), horizontal cells (B, ho), Müller glia (C, mg), bipolar cells (D, bi), amacrine cells (E, am), and RGCs (F–H). Some RGCs expressing NFΔE possess only dendrites (F, arrowheads) or only an axon (G, arrow), whereas some lack all processes (H). Embryos were cotransfected with GAP-GFP, and the distribution of NFΔE (F–H) and GAP-GFP (F′–H′) in RGCs was very similar, illustrating NFΔE is transported through the axodendritic field. I, RGC transfected with GAP-GFP alone, with multiple dendrites (arrowheads) and an axon extending to the ONH (arrow). PE, Pigment epithelium. Scale bar, 25 μm.
Figure 3.
NFΔE and TAF1ΔN impair axon and dendrite initiation and outgrowth from RGCs. Quantitative analysis of GAP-GFP-, NFΔE-, NFΔN-, and TAF1ΔN-expressing RGCs at stage 40. A, The percentage of RGCs with axons was significantly reduced in cells expressing NFΔE or TAF1ΔN compared with RGCs expressing GAP-GFP. B, C, Although many axons from GAP-GFP- or NFΔN-expressing RGCs reached the tectum, the percentage of axons reaching the tectum was significantly smaller in NFΔE- or TAF1ΔN-expressing cells (B), and these RGCs had on average significantly shorter axons (C). D–F, The number of RGCs with dendrites was similar between all sample groups (D), but RGCs expressing NFΔE or TAF1ΔN had significantly fewer (E) and shorter (F) dendrites per cell. Numbers in bars indicate RGCs analyzed for each group. *p < 0.0005, χ2 test; **p < 0.001, Kruskal–Wallis test.
Figure 4.
Distribution of axon lengths from transfected RGCs. Axon lengths from all samples were pooled into 100 μm bins. NFΔE- or TAF1ΔN-expressing RGCs do not accumulate at a specific point in the optic pathway, suggesting a general impairment in axonogenesis.
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