Tead transcription factors differentially regulate cortical development

Tanzila Mukhtar,Pascal Grobecker,Jeremie Breda,Christian Beisel,Zahra Karimaddini,Verdon Taylor,Dagmar Iber,Erik Van Nimwegen,Alice Grison

doi:10.1038/s41598-020-61490-5

Tanzila Mukhtar, Pascal Grobecker + Show 7 more

Open Access

https://doi.org/10.1038/s41598-020-61490-5

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Abstract

Neural stem cells (NSCs) generate neurons of the cerebral cortex with distinct morphologies and functions. How specific neuron production, differentiation and migration are orchestrated is unclear. Hippo signaling regulates gene expression through Tead transcription factors (TFs). We show that Hippo transcriptional coactivators Yap1/Taz and the Teads have distinct functions during cortical development. Yap1/Taz promote NSC maintenance and Satb2+ neuron production at the expense of Tbr1+ neuron generation. However, Teads have moderate effects on NSC maintenance and do not affect Satb2+ neuron differentiation. Conversely, whereas Tead2 blocks Tbr1+ neuron formation, Tead1 and Tead3 promote this early fate. In addition, we found that Hippo effectors regulate neuronal migration to the cortical plate (CP) in a reciprocal fashion, that ApoE, Dab2 and Cyr61 are Tead targets, and these contribute to neuronal fate determination and migration. Our results indicate that multifaceted Hippo signaling is pivotal in different aspects of cortical development.

Highlights

Www.nature.com/scientificreports in the light that Yap[1] localization was not obviously affected in Fat[4], Dchs double-mutant mice and Fat[4] may not be able to activate Hippo signaling in some cell-types[14,16]
We show by gain and loss of function experiments that Tead[1] and Tead[3] are functionally similar but their effects on cortical development are distinct to that of Tead[2]
We show that ApoE, Cyr[61] and Dab[2], which regulate activity of the Reelin receptor ApoER2, partially convey the Tead-mediated mutant phenotypes we observed during cortical development

Summary

Introduction

Www.nature.com/scientificreports in the light that Yap[1] localization was not obviously affected in Fat[4], Dchs double-mutant mice and Fat[4] may not be able to activate Hippo signaling in some cell-types[14,16]. Overexpression experiments expressing Yap[1] and Taz in NSCs implied that Tead[2] is the mediator in their control of neural progenitor proliferation and neurogenesis[20]. Fat1/Fat[4] double knockout mice show similar neural tube closure defects suggesting redundancy in these two receptors, the downstream mechanisms causing these phenotypes are not understood[13]. We find that the expression of Hippo signaling components is highly dynamic during cortical development within the NSC, basal progenitor (BP) and neuronal lineages. Whereas in many systems Tead factors are redundant[21], they show specific cell-type and temporal dynamics in their expression during cortical development. We show that ApoE, Cyr[61] and Dab[2], which regulate activity of the Reelin receptor ApoER2, partially convey the Tead-mediated mutant phenotypes we observed during cortical development. Our data indicate multiple and specific roles of Hippo signaling effectors during cortical neurogenesis and provide a link between the Hippo and the Reelin pathways

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