Abstract
Wnt signaling plays a major role in early neural development. An aberrant activation in Wnt/β-catenin pathway causes defective anteroposterior patterning, which results in neural tube closure defects (NTDs). Changes in folate metabolism may participate in early embryo fate determination. We have identified that folate deficiency activated Wnt/β-catenin pathway by upregulating a chorion-specific transcription factor Gcm1. Specifically, folate deficiency promoted formation of the Gcm1/β-catenin/T-cell factor (TCF4) complex formation to regulate the Wnt targeted gene transactivation through Wnt-responsive elements. Moreover, the transcription factor Nanog upregulated Gcm1 transcription in mESCs under folate deficiency. Lastly, in NTDs mouse models and low-folate NTDs human brain samples, Gcm1 and Wnt/β-catenin targeted genes related to neural tube closure are specifically overexpressed. These results indicated that low-folate level promoted Wnt/β-catenin signaling via activating Gcm1, and thus leaded into aberrant vertebrate neural development.
Highlights
Neural tube defects (NTDs) are severe birth defects thought to be associated with genetic and environmental factors[1], resulted from the failure of neural tube closure during first trimester
We further showed that Gcm[1] is strongly expressed in low-folate NTDs samples, which is accompanied by upregulation of Wnt/ β-catenin targeted genes related to neural tube closure
The transcription of TOP/FOP exhibited 2.4-fold higher level with Gcm[1] overexpression, which was consistent with the positive control group treated with LiCl (Fig. 3g). These results suggested that an aberrant increased in Gcm[1] expression activated Wnt signaling by mediating Gcm1/β-catenin/TCF4 tri-complex formation
Summary
Neural tube defects (NTDs) are severe birth defects thought to be associated with genetic and environmental factors[1], resulted from the failure of neural tube closure during first trimester. Prepregnancy supplementation with folate can prevent 30–70% of NTDs2, but still the mechanism behind its prevention remains unclear. The activation of Wnt signaling is essential for upregulation of Gcm[1] and ST cell specification. Wnt10b is involved in the activation of β-catenin/GCM1 pathway during the process of BeWo cell fusion after forskolin/hCG treatment[9]. These findings suggested that Gcm[1] may be linked with Wnt signaling pathway, which can affect its activity to control cell fate
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