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

Abstract

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 Foxp2 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 Fzd7 was silenced, we found decreased Foxp2 protein expression and increased Foxp1 protein expression, respectively. The Fzd7 silencing also disrupted the migration of neocortical glutamatergic neurons. In contrast, Fzd7 overexpression reversed the pattern of migratory defects and Foxp protein expression that we found in the Fzd7 silencing. We further discovered that Fzd7 is required for Wnt3-induced Foxp2 mRNA translation. Surprisingly, we also determined that the Fzd7 suppression of Foxp1 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.

Translational control in cortical development

“…The dynamically changing populations of mRNAs recruited for intensive translation are functionally related; these sets of mRNAs are enriched for factors involved in transcriptional and translational regulation that are different at distinct time points of neurogenesis. The dynamic "ribosome signature" is influenced by WNT3 signals, released from incoming thalamic axons, which promote Foxp2 translation through its 3'UTR (Kraushar et al, 2014(Kraushar et al, , 2015Popovitchenko et al, 2016;Park et al, 2021).…”

Making sense of mRNA landscapes: Translation control in neurodevelopment

“…These decreased global translation rates are followed by decreases in total bulk ribosomal protein (RP) levels before neurogenesis (Chau et al, 2018) and as neurogenesis proceeds (Kraushar et al, 2015;Kraushar et al, 2021). This global decrease in mRNA translation is contrasted by selective increase in distinct mRNAs such as Foxp1 and Foxp2 (Park et al, 2021). Interestingly, decreased total protein levels of some RPs do not equal their relative decrease in the polysomes as active sites of mRNA translation (Kraushar et al, 2014;Kraushar et al, 2015;Kraushar et al, 2021).…”

“…Thus, after transcriptional priming of the developing cell, mRNAs within this cell are translationally poised, awaiting signals to unlock protein synthesis. Within the developing prenatal neocortex, protein synthesis of Foxp1 and Foxp2 transcription factor mRNAs has been shown to be tightly regulated in the neurons and oligodendrocytes of the developing neocortex by the timed extracellular factor, Wnt3, and an RNA binding protein (RBP), HuR/Elavl1 (Kraushar et al, 2015;Park et al, 2021;Popovitchenko et al, 2016). Protein synthesis is also highly controlled in prenatal neocortical progenitors by repressive complex involving eIF4E1, 4E-T, and Pumillio 2 that coordinately repress synthesis of proteins that regulate neurogenesis (D'Arcy & Silver, 2020;Yang et al, 2014;Zahr et al, 2018;Zahr et al, 2019).…”

Evolution of the Neocortex Through RNA-Binding Proteins and Post-transcriptional Regulation

“…These cell-intrinsic players, together with extrinsic factors, play an essential role in modulating the information flow from genes to proteins, thereby participating in the diversification of cell function from a fixed numbers of genes ( Halbeisen et al, 2008 ; Ascenzi and Bony, 2017 ). Such coordinated regulatory activity of intrinsic and extrinsic patterns is particularly relevant to instruct the sequential flow of neocortical development ( Kraushar et al, 2015 ; Yuzwa and Miller, 2017 ; Park et al, 2021a , b ).…”