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The aristaless-related gene, Arx, plays a fundamental role in patterning the brain in humans and mice. Arx mutants exhibit lissencephaly among other anomalies. We have cloned a Xenopus aristaless homolog that appears to define specific regions of the developing forebrain. xArx2 is transcribed in blastula through neurula stages, and comes to be restricted to the ventral and lateraltelencephalon, lateraldiencephalon, neural floor plate of the anteriorspinal cord, and somites. In this respect, Arx2 expresses in regions similar to Arx with the exception of the somites. Overexpression enlarges the telencephalon, and interference by means of antisense morpholino-mediated translation knockdown reduces growth of this area. Overexpression and inhibition studies demonstrate that misregulation of xArx2 imposes dire consequences upon patterns of differentiation not only in the forebrain where the gene normally expresses, but also in more caudal brain territories and derivatives as well. This suggests that evolutionary changes that expanded Arx-expression from ventral to dorsal prosencephalon might be one of the determinants that marked development and expansion of the telencephalon.
FIG. 4. Expression of xArx2 during Xenopus development. At blastula stage (a), xArx2 is observed in dorsal blastomeres. Expression later restricts to a pair of distinct stripes in the anterior neural plate, and more diffusely in the apical neural ridge (b arrow, which later refines to a light crescent, arrow in c). Expression is later observed in somites (d,e), and presumptive forebrain (f,g), which consequently refines to dien- cephalon (di) and telencephalon (tel) (g). In cleared embryos, expression is detected in the anterior neural tube (h). Cross sections of Xeno- pus embryos demonstrate expression of xArx2 in the ventral and lateral telencephalon (i), lateral diencephalon (j). In situ hybridization using Arx and Arx2-specific probes show distinct expression patterns (k). Unilaterally injected Arx2 morpholino (arrows) perturbs expression of Arx2 (l). Reproduced with permission of the Publisher, John Wiley & Sons.
FIG. 5. Double stained in situ hybridizations show that Arx2 is expressed caudal to telencephalon markers FoxG1/Xbf1 (a) and Rx (b), but rostral to diencephalon/mesencephalon marker Otx1 (c) and isthmus marker engrailed (d) Reproduced with permission of the Publisher, John Wiley & Sons.
FIG. 7. Arx2 misexpression perturbs forebrain development. Unilaterally injected embryos develop enlarged forebrains if injected at the 2-cell stage with Arx2 transcript (a), diminished forebrains if injected with antisense morpholinos (b). Asymmetrical growth is particularly evident in longitudinal sections: ectopic expression of xArx2 expands the forebrain growth relative to contralateral tissues in Hoechst- stained sections (c), and inhibition by antisense morpholino inhibits growth (d). Reproduced with permission of the Publisher, John Wiley & Sons.
FIG. 8. The effect of misexpression of xArx2 on forebrain markers FoxG1/XBF1, Rx1, and Pax6. Following unilateral injection at the 2-cell stage with xArx2 mRNA (400 pg) or xArx2 antisense morpholino oligonucleotides (18 ng xArx2-MO), embryos were stained for marker gene expression at late neurula (a) or later during organogenesis (a00). FoxG1/XBF1 following transcript or morpholino injection- a, a0 and b, b0 respectively; Rx1 expression following transcript or morpholino injection c, c0 and d, d0 respectively; Pax6 expression following transcript or morpholino injection e, e0, and f, f0 respectively. Reproduced with permission of the Publisher, John Wiley & Sons.
FIG. 9. The effect of misexpression of xArx2 on midbrain markers xOtx2 and xPax2. As before, embryos were unilaterally injected on the left side (right side of picture). Marker gene perturbation is induced by xArx2 mRNA (400 pg) or xArx2 antisense morpholino oligonucleotides (18 ng xArx2-MO) at early (a) and later (a00) developmental stages and are shown from an anterior perspective. xArx2 transcript or anti- sense morpholino injected embryos were stained for xOtx2 (a, a0, and b, b0 respectively), or for xPax2 (c, c0, and d, d0 respectively). Reproduced with permission of the Publisher, John Wiley & Sons.
FIG. 10. The effect of misexpression of xArx2 on hindbrain markers Gbx2 and Krox-20. As before, embryos were unilaterally injected on the left side (right side of picture). Marker gene perturbation is induced by xArx2 mRNA (400 pg) or xArx2 antisense morpholino oligonucleo- tides (18 ng xArx2-MO) at early (a) and later (a00) developmental stages and are shown from an anterior perspective. xArx2 transcript or antisense morpholino injected embryos were stained for Gbx2 (a, a0, and b, b0 respectively), or for Krox-20 (c, c0, and d, d0 respectively). Reproduced with permission of the Publisher, John Wiley & Sons.
