FoxO6 affects Plxna4-mediated neuronal migration during mouse cortical development

Abstract

The forkhead transcription factor FoxO6 is prominently expressed during development of the murine neocortex. However, its function in cortical development is as yet unknown. We now demonstrate that cortical development is altered in FoxO6 +/− and FoxO6 −/− mice, showing migrating neurons halted in the intermediate zone. Using a FoxO6-directed siRNA approach, we substantiate the requirement of FoxO6 for a correct radial migration in the developing neocortex. Subsequent genome-wide transcriptome analysis reveals altered expression of genes involved in cell adhesion, axon guidance, and gliogenesis upon silencing of FoxO6. We then show that FoxO6 binds to DAF-16-binding elements in the Plexin A4 (Plxna4) promoter region and affects Plxna4 expression. Finally, ectopic Plxna4 expression restores radial migration in FoxO6 +/− and siRNA-mediated knockdown models. In conclusion, the presented data provide insights into the molecular mechanisms whereby transcriptional programs drive cortical development.

FOXO in Neural Cells and Diseases of the Nervous System

“…The same is mainly true of the FOXO6 knockout mouse although FOXO6 knockout neurons do have a somewhat decreased dendritic spine density (Salih et al, 2012). They also have defects in the radial migration of cortical neurons (Paap et al, 2016). Interestingly, combined knockdown of FOXO1/3/6 by shRNA in vitro and in vivo results in Pak1 loss and severe defects in the establishment of neural polarity (de la Torre-Ubieta et al, 2010).…”

Integrative genomic analysis of early neurogenesis reveals a temporal genetic program for differentiation and specification of preplate and Cajal-Retzius neurons

“…Cluster 1 gene Rnd2 functions in the downstream of Neurog2 to promote neuron migration (36). Other genes in these three clusters such as Plxna4 is also reported to regulate neuronal migration in neocortex development ( Fig 1E and F) (37). Thus, Cluster 1, 5, 7 (C157 in short) genes might be involved in initial transition from progenitor cells to neuronal differentiation.…”

PlexinA4-Semaphorin3A mediated crosstalk between main cortical interneuron classes is required for superficial interneurons lamination

“…Expression of the gene coding for the receptor PlexinA4 (Plxna4) had a similar dynamic expression to Htr3a (Fig. 1B left) and was of a particular interest since it has been shown to regulate neural cell guidance (Matsuoka et al 2012;Hatanaka et al 2019;Waimey et al 2008;Tomooka 2012, 2013;Paap et al 2016). Hypothesizing a role for Plxna4 in the guidance and lamination of hINs, we first verified its expression in hINs along their migration to the cortex and as they transited through the different cortical compartments towards their final laminar positions.…”

“…Although Plxna4 has been involved in radial migration of PNs in rodents Paap et al 2016;Hatanaka et al 2019), at P21 the overall cortical architecture and distribution of superficial layer PNs in Plxna4 -/brains appeared unchanged as compared to controls (Supp. Fig.…”

“…Here we show that in hINs Plxna4 upregulation during the CP invasion is dependent of Htr3a, suggesting a link between the serotonergic system and further events of hINs guidance relying on PLXNA4. PLXNA4-related mechanisms have been extensively described for axon guidance (Mitsogiannis, Little, and Mitchell 2017;Runker et al 2008;Schwarz et al 2008;Suto et al 2005;Yaron et al 2005) as well as in glial Tomooka 2012, 2013) and neuronal migration (Paap et al 2016). In the field of axonal guidance, it has been proposed that SEMA3A has a favored affinity for NRP1 which in turn pairs principally with PLXNA4, whereas PLXNA3/NRP2 complexes transduce SEMA3F signaling (Suto et al 2005;Yaron et al 2005).…”