Abstract
During mouse neocortical development, the Wnt–β-catenin signaling pathway plays essential roles in various phenomena including neuronal differentiation and proliferation of neural precursor cells (NPCs). Production of the appropriate number of neurons without depletion of the NPC population requires precise regulation of the balance between differentiation and maintenance of NPCs. However, the mechanism that suppresses Wnt signaling to prevent premature neuronal differentiation of NPCs is poorly understood. We now show that the HMG box transcription factor Tcf3 (also known as Tcf7l1) contributes to this mechanism. Tcf3 is highly expressed in undifferentiated NPCs in the mouse neocortex, and its expression is reduced in intermediate neuronal progenitors (INPs) committed to the neuronal fate. We found Tcf3 to be a repressor of Wnt signaling in neocortical NPCs in a reporter gene assay. Tcf3 bound to the promoter of the proneural bHLH gene Neurogenin1 (Neurog1) and repressed its expression. Consistent with this, Tcf3 repressed neuronal differentiation and increased the self-renewal activity of NPCs. We also found that Wnt signal stimulation reduces the level of Tcf3, and increases those of Tcf1 (also known as Tcf7) and Lef1, positive mediators of Wnt signaling, in NPCs. Together, these results suggest that Tcf3 antagonizes Wnt signaling in NPCs, thereby maintaining their undifferentiated state in the neocortex and that Wnt signaling promotes the transition from Tcf3-mediated repression to Tcf1/Lef1-mediated enhancement of Wnt signaling, constituting a positive feedback loop that facilitates neuronal differentiation.
Highlights
The canonical Wnt–b-catenin signaling pathway has a variety of roles in stem cell regulation during development and throughout adult life, ranging from maintenance of multipotency to induction of fate commitment [1,2]
We found Tcf3 mRNA was expressed in the ventricular zone (VZ) but not in the intermediate zone (IMZ) or the cortical plate (CP) of the mouse neocortex at E11.5 and E14.5 (Fig. 1A,A’), consistent with previous reports [28,34,35]
Since the neocortical VZ contains undifferentiated Neural precursor cells (NPCs) and differentiating neurons (that include intermediate neuronal progenitors (INPs) and postmitotic neurons), we examined which of these cell populations expresses Tcf3
Summary
The canonical Wnt–b-catenin signaling pathway has a variety of roles in stem cell regulation during development and throughout adult life, ranging from maintenance of multipotency to induction of fate commitment [1,2]. The Wnt–b-catenin pathway is active in the neocortical ventricular zone (VZ), where NPCs reside and start to differentiate, and plays critical roles in regulating proliferation of neocortical NPCs [6,7,8,9,10]. Since the balance between maintenance and differentiation of NPCs is essential for generating an appropriate number of neurons and for establishing the fine brain architecture, the activity of the Wnt–b-catenin pathway should be precisely regulated. Many extracellular and intracellular molecules have been identified to regulate the Wnt–bcatenin pathway, how the activity of this pathway is controlled in NPCs is still largely unknown
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