Extrinsic Regulators of mRNA Translation in Developing Brain: Story of WNTs

• Main Authors: Yongkyu Park, Midori Lofton, Diana Li, Mladen-Roko Rasin
• Format: Article
• Language: English
• Published: MDPI AG 2021-01-01
• Series: Cells
• Subjects: neocortical development; ligand Wnt3 signaling; Fzd7 receptor; Foxp transcription factor; mRNA translation regulation; morphogen factor
• Online Access: https://www.mdpi.com/2073-4409/10/2/253

Extrinsic molecules such as morphogens can regulate timed mRNA translation events in developing neurons. In particular, Wingless-type MMTV integration site family, member 3 (Wnt3), was shown to regulate the translation of <i>Foxp2 </i>mRNA encoding a Forkhead transcription factor P2 in the neocortex. However, the Wnt receptor that possibly mediates these translation events remains unknown. Here, we report Frizzled member 7 (Fzd7) as the Wnt3 receptor that lays downstream in Wnt3-regulated mRNA translation. Fzd7 proteins co-localize with Wnt3 ligands in developing neocortices. In addition, the Fzd7 proteins overlap in layer-specific neuronal subpopulations expressing different transcription factors, Foxp1 and Foxp2. When <i>Fzd7 </i>was silenced, we found decreased Foxp2 protein expression and increased Foxp1 protein expression, respectively. The <i>Fzd7</i> silencing also disrupted the migration of neocortical glutamatergic neurons. In contrast, <i>Fzd7</i> overexpression reversed the pattern of migratory defects and Foxp protein expression that we found in the <i>Fzd7</i> silencing. We further discovered that Fzd7 is required for Wnt3-induced <i>Foxp2</i> mRNA translation. Surprisingly, we also determined that the <i>Fzd7 </i>suppression of <i>Foxp1</i> protein expression is not Wnt3 dependent. In conclusion, it is exhibited that the interaction between Wnt3 and Fzd7 regulates neuronal identity and the Fzd7 receptor functions as a downstream factor in ligand Wnt3 signaling for mRNA translation. In particular, the Wnt3-Fzd7 signaling axis determines the deep layer Foxp2-expressing neurons of developing neocortices. Our findings also suggest that Fzd7 controls the balance of the expression for Foxp transcription factors in developing neocortical neurons. These discoveries are presented in our manuscript within a larger framework of this review on the role of extrinsic factors in regulating mRNA translation.