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Genesis
2002 Jun 01;332:86-96. doi: 10.1002/gene.10095.
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Axes establishment during eye morphogenesis in Xenopus by coordinate and antagonistic actions of BMP4, Shh, and RA.
Sasagawa S
,
Takabatake T
,
Takabatake Y
,
Muramatsu T
,
Takeshima K
.
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We have examined the roles of BMP4, Shh, and retinoic acid in establishing the proximal-distal and dorsal-ventral axes in the developing Xenopus eye. Misexpression of BMP4 caused the absence of an optic stalk and the expansion of dorsal and distal markers, tbx2/3/5, and pax6, at the expense of ventral and proximal markers vax2 and pax2. When Shh or Noggin, an antagonist of BMPs, was misexpressed, the reverse expression patterns of these marker genes were observed. These results suggest that BMP4 is involved in the specification of not only dorsal in the optic cup but also distal in the optic vesicle. Because Shh did not suppress bmp4 expression, unlike Noggin, Shh and BMP4 may antagonistically regulate common downstream genes in developing eye. We also found the difference between the effects of Shh and retinoic acid, another possible ventralizing factor, suggesting that Shh could promote ventralization independently of retinoic acid. These findings provide important clues to the coordinate and antagonistic actions of BMP4, Shh, and retinoic acid in axes specifications of Xenopus eyes.
FIG. 2. Misexpression of Noggin represses dorsal fates. Dorsal markers tbx2/3/5 disappeared (a). Ventral marker vax2 expanded over the dorsal side (g, h). At stage 42 embryo, the choroid fissure was observed but no lens was detected (i). In situ hybridization was performed at stage 30. Right side in the same embryo: control. Reproduced with permission of the Publisher, John Wiley & Sons.
FIG. 3. Overexpression of Shh causes ventral specifications. Dorsal markers tbx2/3/5 disappeared (a). Expanding expres- sion of ventral marker vax2 reached almost the dorsal end of the optic vesicle (g, h). Although the eye became deformed and small by ectopic expression of Shh, a meager lens structure was confirmed in all embryos examined (ik). In situ hybridization was performed at stage 30. Right side in the same embryo: control. . Reproduced with permission of the Publisher, John Wiley & Sons.
FIG. 4. BMP4 is involved in P-D axis formation of the eye. Overexpression of BMP4 causes abnormal connection between retinal pigment epithelium and brain including loss of the optic stalk at stage 46 (A: a, b, c, dorsal view; A: d, e, lateral view). At the stage 30 embryos, proximal marker pax2 was repressed (B: b) and distal marker pax6 was expanded (B: f) by overexpression of BMP4. Conversely, misexpression of Shh or Noggin promotes the expansion of pax2 (B: c, d) and the suppression of pax6 (B: g, h). In situ hybridization was performed at stage 30.Reproduced with permission of the Publisher, John Wiley & Sons.
FIG. 5. bmp4 expression in the optic vesicle required both Shh and its own signal. Whereas Shh overexpression rather reinforced the expression of bmp4 (a, b), misexpression of Noggin, an antagonist of BMP, clearly repressed the expression of bmp4 (c, d). In situ hybridization was performed at stage 30. Right side in the same embryo: control. Reproduced with permission of the Publisher, John Wiley & Sons.
FIG. 6. RA had differential effects on D-V patterning of eye. Stage 16 embryos were treated with 1 M RA and cultured until stage 30 to perform in situ hybridization or stage 42 to verify the malformation of eye. Dorsal marker tbx2/3/5 (c) and bmp4 (a, b) were scarcely suppressed by RA, although the ventral expression borders expanded ventrally (c) and such expression more or less reoriented to the nasal side (ah). On the other hand, ventral marker vax2 was expanded dorsally (i, j). The choroids fissure of RA-treated embryo remained wide open (k, l) while the presence of the meager lens was confirmed (k). Reproduced with permission of the Publisher, John Wiley & Sons.
FIG. 7. The repressive effect of RA on shh and Shh-responsive genes, ptc1/2, was relatively weak or almost negligible in the forebrain (a: arrowhead), whereas RA treatment resulted in their strong repression in the caudal brain and anterior neural tube (a: arrow). In situ hybridization was performed at stage 30. Embryos were cleared by benzyl alcohol-benzyl benzoate. Reproduced with permission of the Publisher, John Wiley & Sons.
