The neural crest (NC) is crucial for the evolutionary diversification of vertebrates. NC cells are induced at the neural plate border by the coordinated action of several signaling pathways, including Wnt/β-catenin. NC cells are normally generated in the posterior neural plate border, whereas the anterior neural fold is devoid of NC cells. Using the mouse model, we show here that active repression of Wnt/β-catenin signaling is required for maintenance of neuroepithelial identity in the anterior neural fold and for inhibition of NC induction. Conditional inactivation of Tcf7l1, a transcriptional repressor of Wnt target genes, leads to aberrant activation of Wnt/β-catenin signaling in the anterior neuroectoderm and its conversion into NC. This reduces the developing prosencephalon without affecting the anterior-posterior neural character. Thus, Tcf7l1 defines the border between the NC and the prospective forebrain via restriction of the Wnt/β-catenin signaling gradient.

• Klíčová slova
• Forebrain, Mouse, Neural crest, Tcf/Lef, Wnt signaling, Zebrafish,
• MeSH
• beta-katenin metabolismus   MeSH
• biologické markery metabolismus   MeSH
• buněčný rodokmen * MeSH
• crista neuralis cytologie   metabolismus   MeSH
• dánio pruhované metabolismus   MeSH
• defekty neurální trubice metabolismus   patologie   MeSH
• delece genu MeSH
• fenotyp MeSH
• integrasy metabolismus   MeSH
• lidé MeSH
• myši transgenní MeSH
• přední mozek embryologie   metabolismus   MeSH
• protein 1 podobný transkripčnímu faktoru 7 metabolismus   MeSH
• proteiny dánia pruhovaného metabolismus   MeSH
• represorové proteiny metabolismus   MeSH
• signální dráha Wnt MeSH
• transdiferenciace buněk MeSH
• transkripční faktor AP-2 metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• beta-katenin MeSH
• biologické markery MeSH
• Cre recombinase MeSH Prohlížeč
• integrasy MeSH
• protein 1 podobný transkripčnímu faktoru 7 MeSH
• proteiny dánia pruhovaného MeSH
• represorové proteiny MeSH
• Tcf7l1 protein, mouse MeSH Prohlížeč
• tcf7l1a protein, zebrafish MeSH Prohlížeč
• transkripční faktor AP-2 MeSH

A precisely balanced activity of canonical Wnt signaling is essential for a number of biological processes and its perturbation leads to developmental defects or diseases. Here, we demonstrate that alternative isoforms of the KDM2A and KDM2B lysine demethylases have the ability to negatively regulate canonical Wnt signaling. These KDM2A and KDM2B isoforms (KDM2A-SF and KDM2B-SF) lack the N-terminal demethylase domain, but they still have the ability to bind to CpG islands in promoters and to interact with their protein partners via their other functional domains. We have observed that KDM2A-SF and KDM2B-SF bind to the promoters of axin 2 and cyclin D1, two canonical Wnt signaling target genes, and repress their activity. Moreover, KDM2A-SF and KDM2B-SF are both able to strongly repress a Wnt-responsive luciferase reporter. The transcriptional repression mediated by KDM2A-SF and KDM2B-SF, but also by KDM2A-LF, is dependent on their DNA binding domain, while the N-terminal demethylase domain is dispensable for this process. Surprisingly, KDM2B-LF is unable to repress both the endogenous promoters and the luciferase reporter. Finally, we show that both KDM2A-SF and KDM2B-SF are able to interact with TCF7L1, one of the transcriptional mediators of canonical Wnt signaling. KDM2A-SF and KDM2B-SF are thus likely to negatively affect the transcription of canonical Wnt signaling target genes by binding to their promoters and by interacting with TCF7L1 and other co-repressors.

• MeSH
• CpG ostrůvky MeSH
• cyklin D1 genetika   metabolismus   MeSH
• doména Jumonji s histondemethylasami genetika   metabolismus   MeSH
• F-box proteiny genetika   metabolismus   MeSH
• HEK293 buňky MeSH
• lidé MeSH
• lysin genetika   metabolismus   MeSH
• promotorové oblasti (genetika) * MeSH
• protein - isoformy MeSH
• protein 1 podobný transkripčnímu faktoru 7 genetika   metabolismus   MeSH
• regulace genové exprese * MeSH
• signální dráha Wnt * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• CCND1 protein, human MeSH Prohlížeč
• cyklin D1 MeSH
• doména Jumonji s histondemethylasami MeSH
• F-box proteiny MeSH
• KDM2A protein, human MeSH Prohlížeč
• lysin MeSH
• protein - isoformy MeSH
• protein 1 podobný transkripčnímu faktoru 7 MeSH
• TCF7L1 protein, human MeSH Prohlížeč

Generation of neurons in the embryonic neocortex is a balanced process of proliferation and differentiation of neuronal progenitor cells. Canonical Wnt signalling is crucial for expansion of radial glial cells in the ventricular zone and for differentiation of intermediate progenitors in the subventricular zone. We detected abundant expression of two transcrtiption factors mediating canonical Wnt signalling, Tcf7L1 and Tcf7L2, in the ventricular zone of the embryonic neocortex. Conditional knock-out analysis showed that Tcf7L2, but not Tcf7L1, is the principal Wnt mediator important for maintenance of progenitor cell identity in the ventricular zone. In the absence of Tcf7L2, the Wnt activity is reduced, ventricular zone markers Pax6 and Sox2 are downregulated and the neuroepithelial structure is severed due to the loss of apical adherens junctions. This results in decreased proliferation of radial glial cells, the reduced number of intermediate progenitors in the subventricular zone and hypoplastic forebrain. Our data show that canonical Wnt signalling, which is essential for determining the neuroepithelial character of the neocortical ventricular zone, is mediated by Tcf7L2.

• Klíčová slova
• Neocortex, Neurogenenesis, Tcf7L1, Tcf7L2, Wnt signalling,
• MeSH
• buněčná diferenciace genetika   MeSH
• chlorid-hydrogenuhličitanové antiportéry MeSH
• down regulace genetika   MeSH
• embryo savčí MeSH
• hipokampus cytologie   embryologie   MeSH
• mutace genetika   MeSH
• myši transgenní MeSH
• myši MeSH
• neokortex cytologie   embryologie   MeSH
• nervové kmenové buňky fyziologie   MeSH
• neurogeneze fyziologie   MeSH
• neuroglie MeSH
• neurony fyziologie   MeSH
• počet buněk MeSH
• proliferace buněk genetika   MeSH
• protein 2 podobný transkripčnímu faktoru 7 genetika   metabolismus   MeSH
• proteiny T-boxu metabolismus   MeSH
• proteiny Wnt metabolismus   MeSH
• retinální gangliové buňky fyziologie   MeSH
• signální transdukce genetika   MeSH
• transkripční faktory SOXB1 metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chlorid-hydrogenuhličitanové antiportéry MeSH
• Eomes protein, mouse MeSH Prohlížeč
• protein 2 podobný transkripčnímu faktoru 7 MeSH
• proteiny T-boxu MeSH
• proteiny Wnt MeSH
• Sox2 protein, mouse MeSH Prohlížeč
• Tcf7l2 protein, mouse MeSH Prohlížeč
• transkripční faktory SOXB1 MeSH

T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) proteins (TCFs) from the High Mobility Group (HMG) box family act as the main downstream effectors of the Wnt signaling pathway. The mammalian TCF/LEF family comprises four nuclear factors designated TCF7, LEF1, TCF7L1, and TCF7L2 (also known as TCF1, LEF1, TCF3, and TCF4, respectively). The proteins display common structural features and are often expressed in overlapping patterns implying their redundancy. Such redundancy was indeed observed in gene targeting studies; however, individual family members also exhibit unique features that are not recapitulated by the related proteins. In the present viewpoint, we summarized our current knowledge about the specific features of individual TCFs, namely structural-functional studies, posttranslational modifications, interacting partners, and phenotypes obtained upon gene targeting in the mouse. In addition, we employed several publicly available databases and web tools to evaluate the expression patterns and production of gene-specific isoforms of the TCF/LEF family members in human cells and tissues.

• Klíčová slova
• Fantom5, GTEx, Wnt signaling, splicing isoforms, the Cancer Genome Atlas,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH