Cao Y et al. (2002), XETOR regulates the size of the proneural domai...

XB-ART-6384

Mech Dev 2002 Nov 01;1191:35-44. doi: 10.1016/s0925-4773(02)00285-x.

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XETOR regulates the size of the proneural domain during primary neurogenesis in Xenopus laevis.

Cao Y , Zhao H , Grunz H .

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The interaction between early proneural genes and lateral inhibition determines the number of primary neurons. The mechanism for regulating the size of the proneural domain, however, has not been clarified. We show here that inhibition of the function of XETOR in Xenopus, a homolog of human oncoprotein ETO/MTG8, leads to a neurogenic phenotype of expanded proneural domain without alteration in the density of primary neurons. This result suggests that XETOR is a prerequisite for regulating the size of the proneural domain. We further show that such a regulation is accomplished by establishing a negative feedback loop between XETOR and proneural genes except Xngnr-1, as well as by antagonism between XETOR and lateral inhibition.

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Species referenced: Xenopus laevis
Genes referenced: ascl2 cbfa2t2 dll1 esr1 hes5 myt1 neurod1 neurod4 neurog2 nrarp runx1 sox3 tubb2b
GO keywords: nervous system development
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	Fig. 3. Spatial expression of XETOR during embryogenesis. (A, B, D, E) XETOR is expressed in three stripes on each side of dorsal midline, as well as in the trigeminal ganglia. (C) An expression domain in the presumptive ventral blood island. (F, G) XETOR expression during tailbud stages. (H) Side-by-side comparison between the expression of XETOR and of N-tubulin, showing similar patterns. (I) Transversal section through an embryo hybridized with XETOR and N-tubulin probes confirms the coexpression of the two genes. (A, B, D, E, H) Dorsal view, anterior is up. (C) Ventral view of a neurula as in (B), anterior is up. (F) Dorsal view, anterior is left. (G) Lateral and dorsal view (inset) of a same tailbud, anterior is left. ba, branchial arch; bl, blastopore; i, intermediate stripe; l, lateral stripe; m, medial stripe; mc, mescencephalon; op, olfactory placode; rc, rhombencephalon; re, retina; vbi, ventral blood island.
	Fig. 1. Proneural genes define broader domains than the area where primary neurons occur, and early proneural genes have also broader domains than late ones. Xngnr-1, XMyT1, Xath3, XNeuroD and N-tubulin is expressed at stages 10.5, 11.5, 12, 13.5 and 12.5, respectively.
	Fig. 4. Overexpressed XETOR inhibits primary neuron formation while the neural plate expands. Overexpression of XETOR (A, C, D) or the truncation mutants (E) inhibit the expression of N-tubulin (A), Xaml (C) but expand the expression of Xsox3 (D). (B) A control in which only LacZ was injected. (F) Schematic structures of XETOR and truncation mutants. In all the figures, mRNAs injected are shown in upper right and genes whose expression was detected are shown in lower left. The anterior side of the embryos is up. The injected side is marked with X-gal staining, which reveals light blue, and is also indicated with an asterisk. The same holds true for the following figures. aa, amino acid.
	Fig. 5. XETOR is required for primary neurogenesis. (A) Injection of MOXETOR results in an expansion of lateral stripe of N-tubulin expression without appreciable change in neuron density, and this phenotype is rescued by coinjection of XETOR (C). (B) A control oligo does not affect N-tubulin expression. (D) Blocking lateral inhibition results in an increased density of neurons without change in the size of the proneural domain. (E) Blocking both XETOR and lateral inhibition results in an increased density of primary neurons in the lateral stripe of significantly enlarged size, a distinct phenotype from those in (A) and (D).
	Fig. 6. XETOR and lateral inhibition are mutually repressed and XETOR functions independent of lateral inhibition. (A) Overexpression of XETOR inhibits the expression of X-Delta-1. (B) XETOR expression is inhibited by activated lateral inhibition. (C) When lateral inhibition is blocked, XETOR expression is also augmented. (D) XETOR still represses N-tubulin expression in the absence of lateral inhibition. (E,F) Overexpressed XETOR does not affect the expression of ESR1 and XNAP. (G,H) Extirpation of XETOR does not affect the expression of ESR1 and XNAP, either.
	Fig. 7. (A–H) Crossregulation between the expression of XETOR and proneural genes. Overexpression of Xngnr-1 (A) or Xath3 (B) induces significant ectopic XETOR expression. In turn, overexpression of XETOR does not affect Xngnr-1 expression (C), but inhibits Xath3 expression (D). XETOR expression is also activated or enhanced by overexpressed Xash-3 (E), or XNeuroD (H). Conversely, overexpression of XETOR inhibits the expression of XMyT1 (G), but not Xash-3 (F). (I–R) Overexpression of XETOR inhibits the function of proneural genes, except Xngnr-1. Overexpressed Xngnr-1 (I), Xath3 (K), or XNeuroD (M) induces strong ectopic neuron formation. Overexpressed XETOR does not inhibit the activity of Xngnr-1 (J), but inhibit the activity of Xath3 (L) and XNeuroD (N). The neuron inducing activity of Xash-3 (O) and XMyT1 (Q) is also inhibited by XETOR (P, R).
	Fig. 8. A two-step model for primary neurogenesis. Early proneural genes define a broader proneural domain. Within this domain, the density of primary neurons is determined by the interaction between early proneural genes and lateral inhibition. At stage around 12.5, XETOR is activated also by proneural genes. Due to the antagonism between lateral inhibition and XETOR, it is possible that they can exert their functions in exclusive regions in the proneural domain. The region where XETOR expresses can be restricted as a result of repression effect of XETOR on late proneural genes. Thus lateral inhibition and XETOR comprise a dual inhibitory mechanism for primary neurogenesis.
	cbfa2t2 (core-binding factor, runt domain, alpha subunit 2; translocated to, 2) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 12.5.
	cbfa2t2 (core-binding factor, runt domain, alpha subunit 2; translocated to, 2) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 16, dorsal view, anterior up.
	cbfa2t2 (core-binding factor, runt domain, alpha subunit 2; translocated to, 2) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 24, dorsal view, anterior left.
	cbfa2t2 (core-binding factor, runt domain, alpha subunit 2; translocated to, 2) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 32, lateral view, anterior left, dorsal up. Inset, dorsal view, anterior left.