Tcf3 inhibits spinal cord neurogenesis by regulatingsox4aexpression

Abstract

The Lef/Tcf factor Tcf3 is expressed throughout the developing vertebrate central nervous system (CNS), but its function and transcriptional targets are uncharacterized. Tcf3 is thought to mediate canonical Wnt signaling, which functions in CNS patterning, proliferation and neurogenesis. In this study, we examine Tcf3 function in the zebrafish spinal cord, and find that this factor does not play a general role in patterning, but is required for the proper expression of Dbx genes in intermediate progenitors. In addition, we show that Tcf3 is required to inhibit premature neurogenesis in spinal progenitors by repressing sox4a, a known mediator of spinal neurogenesis. Both of these functions are mediated by Tcf3 independently of canonical Wnt signaling. Together, our data indicate a novel mechanism for the regulation of neurogenesis by Tcf3-mediated repression.

Tcf3 Function Is Required for the Inhibition of Oligodendroglial Fate Specification in the Spinal Cord of Zebrafish Embryos

“…In addition, we found that Tcf3 function in the regulation of gliogenesis is mediated independently of canonical Wnt signaling. Collectively, these results, together with previous reports (Gribble et al, 2009), suggest a novel function for Tcf3 in regulating the timing of neurogenesis and gliogenesis in the spinal cord.…”

“…In this study, Tcf3 loss-offunction mediated by a morpholino oligonucleotide targeted against tcf3 (tcf3 MO) caused premature neurogenesis in the progenitors of the spinal cord. Since Tcf3 functions as a transcriptional repressor in the spinal cord, knock-down of tcf3 by an MO induces the expression of several tcf3 target genes including sox4a and sox11, which are normally repressed by Tcf3 (Gribble et al, 2009). These data suggest that constitutive repression of tcf3 target gene expression by a dominantrepressor form of Tcf3 may inhibit normal neurogenesis in the spinal cord.…”

“…However, several lines of in vivo evidence have shown that Tcf3 acts as a repressor of target genes that are activated not by Wnt signaling, but by other mechanisms (Korinek et al, 1998;Pereira et al, 2006), indicating that Tcf3 function can be regulated by other mechanisms independent of Wnt signaling. A recent study has shown that Wnt-independent Tcf3 function is required to inhibit premature neurogenesis in spinal progenitors by inhibiting Sox4a expression, suggesting that Tcf3 plays a crucial function in regulating the timing of neurogenesis (Gribble et al, 2009). In this study, we show that Tcf3 function is also required for the inhibition of the premature oligodendroglial fate of the spinal precursors, using transgenic zebrafish expressing a dominant repressor form of Tcf3 (ΔTcf3) under the control of a heat-shock inducible promoter.…”

Wnt Signaling in Vertebrate Axis Specification

“…A critical event seems to be TCF3 phosphorylation by HIPK2 allowing one to derepress the target genes (Hikasa et al 2010;Sokol 2011), although in some cases TCF3 is likely to function in a Wnt-independent manner (Cole et al 2008;Gribble et al 2009). Homeodomain-interacting protein kinases (HIPKs) have been shown to function in a context-dependent manner in response to Wnt signaling (Wei et al 2007;Lee et al 2009;Louie et al 2009;Kim et al 2010).…”

“…Although both TCF3 and TCF1 can bind b-catenin and Groucho corepressors Brantjes et al 2001), the two proteins appear to function very differently. TCF3 serves exclusively as a transcriptional repressor, whereas TCF1 is a transcriptional activator (Kim et al 2000;Gradl et al 2002;Houston et al 2002;Merrill et al 2004;Liu et al 2005;Nguyen et al 2006;Gribble et al 2009;Hikasa and Sokol 2011). Additional studies are needed to explain the difference in the activity of TCF1 and TCF3, which is likely caused by a distinct set of interacting partners.…”