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Dev Biol April 15, 2010; 340 (2): 318-28.
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En2, Pax2/5 and Tcf-4 transcription factors cooperate in patterning the Xenopus brain.

Koenig SF , Brentle S , Hamdi K , Fichtner D , Wedlich D , Gradl D .

Among Xenopus Lef/Tcfs, XTcf-4 has an outstanding role. In early development it is located exclusively in the midbrain where it is essential for midbrain and isthmus development. In order to identify transcription factors responsible for the restriction of XTcf-4 expression we isolated a 3.8kb fragment of the XTcf-4 promoter. We found that this promoter fragment is sufficient to mimic endogenous XTcf-4 expression in the midbrain. Characterization of putative binding sites for en2 and pax2/5 revealed that en2, but not pax2/5 directly represses XTcf-4 promoter activity. Gain-of-function experiments in Xenopus embryos confirmed this en2-mediated repression. Loss-of-function experiments demonstrate that both en2 and pax2/5 are essential for endogenous XTcf-4 expression. The primary effect of pax2/5 depletion thereby appears to be a reduced en2 expression at neurula stages. Because en2 can compensate for the depletion of pax2/5, we assume a hierarchical regulation of gene expression in the midbrain/isthmus region with pax2/5 acting upstream of en2. Furthermore, since the XTcf-4 expression domain does not overlap with the expression domains of the isthmus marker genes en2 and pax2/5, we conclude that the knock-down of en2 and pax2/5 results in a downregulation of a paracrine growth factor regulating XTcf-4 expression. We found that the growth factor for this non-cell-autonomous effect of en2 and pax2/5 is wnt-1 acting on the -1437 Lef/Tcf binding site on the XTcf-4 promoter. We provide evidence that the main nuclear wnt transducer for the autoregulation of XTcf-4 is XTcf-1.

PubMed ID: 20171202
Article link: Dev Biol

Species referenced: Xenopus
Genes referenced: en2 lef1 pax2 pax5 tcf4 tcf7 tcf7l1 tcf7l2 tle4 wnt1 wnt5a wnt8a
Morpholinos: en2 MO1 lef1 MO3 lef1 MO4 pax2 MO1 pax2 MO2 pax5 MO1 tcf7 MO1 tcf7l2 MO1

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