Xue XY and Harris WA (2012), Using myc genes to search for stem cells in the...

XB-ART-43043

Dev Neurobiol 2012 Apr 01;724:475-90. doi: 10.1002/dneu.20887.

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Using myc genes to search for stem cells in the ciliary margin of the Xenopus retina.

Xue XY , Harris WA .

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The ciliary marginal zone (CMZ) of fish and frog retinas contains cells that proliferate throughout postembryonic development as the retina grows with increasing body size, indicating the presence of stem cells in this region. However, neither the location nor the molecular identity of retinal stem cells has been identified. Here, we show in Xenopus that c-myc and n-myc are sequentially expressed both during development and in the post-embryonic retina. The c-myc+/n-myc- cells near the extreme periphery of the CMZ cycle more slowly and preferentially retain DNA label compared to their more central cmyc+/n-myc+ neighbors which cycle rapidly and preferentially dilute DNA label. During retinal development c-myc is functionally required earlier than n-myc, and n-myc expression depends on earlier c-myc expression. The expression of c-myc but not n-myc in the CMZ depends on growth factor signaling. Our results suggest that c-myc+/n-myc- cells in the far peripheral CMZ are candidates for a niche-dependent population of retinal stem cells that give rise to more centrally located and rapidly dividing n-myc+ progenitors of more limited proliferative potential. Analysis of homologues of these genes in the zebrafish CMZ suggests that the transition from c-myc to n-myc expression might be conserved in other lower vertebrates whose retinas growth throughout life.

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Species referenced: Xenopus
Genes referenced: ascl1 atoh7 cdk1 cdknx myc mycn pax6 rax rbpms2 ret rpe
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Phenotypes: Xla Wt + AG 1478 (fig.S4.c) [+]

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	Figure 4 c-myc is required earlier during eye development compared to n-myc and it is neces- sary for normal n-myc expression. A: c-myc but not n-myc morpholino reduces early pax6 and Xrx1 expression. G: c-myc and n-myc morpholinos both interfere with cyclin D1, cyclin A2, and cdc2 expression. P: c-myc and n-myc morpholinos both interfere with Xash1, Xash3b, and Xath5 expression. A14: n-myc MO does not affect c-myc expression during early retinogenesis. A58: n-myc expression is reduced or abolished in c-myc morpholino injected retinas when examined from Stage 18 onwards. Dotted rectangles indicate the MO containing side of the embryo into which the MO was injected. Bar: A 1 mm. P 1 mm. A18 1 mm. See also Figure S3 and Table S1.



	Supplementary Figure 4. Growth factor signalling is redundant in the CMZ (A-H) Application of individual and combinations of growth factor inhibitors for 24 hours affects c-myc expression to different degrees, with the triple inhibitor treatment generating the most dramatic phenotype. (I-P) n-myc expression is also affected differently by different combinations of inhibitors after 24-hour-treatment. Bar: 100Î¼m.


	Supplementary Figure 1. c-myc and n-myc are expressed in many of the same tissues during early, mid- and late neurogenesis (A-F) c-myc and n-myc are both expressed in various tissues, especially those of the central nervous system, during development. b: brain, op: optic vesicle, mnc: migrating neural crest, tel: telencephalon, di/mi: diencephalon/midbrain, mhb: midbrain/hindbrain boundary, rh: rhombencephalon, e: eye, pa: pharyngeal arches, ov: otic vesicle, s: somites, fb: forebrain, mi: midbrain. Bars: A-B 1 mm, C-D 1mm, E-F 100Î¼m.