Tead transcription factors differentially regulate cortical development

Abstract

Dagmar iber 3,4 , christian Beisel 5 , erik van nimwegen 2 & Verdon taylor 1* 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. NSCs of the developing cerebral cortex form the ventricular zone (VZ) lining the lumen of the neural tube 1-5. NSCs in the dorsal anterior forebrain are the major source of the projection neurons of the cerebral cortex 4,5. The mechanisms controlling the patterning and cell fate specification of these stem cells during early brain development are not clearly understood. Although various signaling pathways including Notch, Wnt, Shh, FGFs, TGF-β, Retinoic acid, Reelin and Hippo are known to regulate NSC proliferation and to control fate decisions, neurogenesis, and gliogenesis; the crosstalk between the different signaling pathways and the integration of these signals on target genes governing complex cell fate choices is unclear 1-3. Hippo signaling is evolutionarily conserved and a regulator of organ size control and tissue homeostasis 6-9. The pathway is regulated by numerous stimuli including G-protein coupled receptor signaling, mechanical stress, cellular energy status, cell-cell contact and cell-extra-cellular matrix interactions 6-8. Hippo signaling employs a cascade of phosphorylation steps mediated by the kinases Mst1/2 and Lats1/2 8-10. Lats1/2 phosphorylate the transcriptional coregulators Yap1 and Taz to promote cytoplasmic retention and subsequent degradation 6-8. When Hippo signaling is inactive, Yap1/Taz translocate to the nucleus and form multiple complexes with different DNA binding partners including TEADs, SMADs, and Runx TFs (Fig. S1a) 8-10. The Teads are major regulators of Hippo target genes in many systems including cancer 8,11,12. Fat4 and Dchs are receptor and ligand, respectively, of the Hippo pathway in embryonic NSCs. Knockdown of Fat4 results in increased proliferation in the developing nervous system and reduction of neuronal differentiation 13,14. Mutations in FAT4 and DCHS cause Van Maldergem syndrome in humans, an autosomal-recessive disorder characterized by in...

Transcriptional Regulators and Human-Specific/Primate-Specific Genes in Neocortical Neurogenesis

“…Similar to sustained Pax6 expression, but in contrast to Insm1 overexpression, the increased level of BPs observed upon conditional expression of a constitutively-active YAP in the BP lineage showed a decreased proportion of Tbr2+ and an increased proportion of Sox2+ BPs. A similar result of increased proliferation in the SVZ was reported in a very recent, independent study in which Yap mRNA (mYAP) instead of constitutively-active YAP was overexpressed in the NPCs of embryonic mouse neocortex [ 110 ]. However, in contrast to Kostic et al [ 109 ], Mukhtar et al [ 110 ] did not report a decrease in Tbr2+ cells in the SVZ when mYAP was overexpressed.…”

“…A similar result of increased proliferation in the SVZ was reported in a very recent, independent study in which Yap mRNA (mYAP) instead of constitutively-active YAP was overexpressed in the NPCs of embryonic mouse neocortex [ 110 ]. However, in contrast to Kostic et al [ 109 ], Mukhtar et al [ 110 ] did not report a decrease in Tbr2+ cells in the SVZ when mYAP was overexpressed.…”

Transcription factor motifs associated with anterior insula gene-expression underlying mood disorder phenotypes

“…We receptor binding TF activity that has been implicated in mood disorders (Zhou et al 2009;Shi et al 20011;Shyn et al 2011) (Mukhtar et al 2020). Furthermore, KLF11 (Duncan et al 2012;Duncan et al 2015;Harris et al 2015;Kollert et al 2020), SP1 (Brewer et al 2004;Tamayo et al 2009;Pinacho et al 2011;Fuste et al 2013;Saucedo-Uribe et al 2019;Hung et al 2020), andSP4 (Zou et al 2009;Fuste et al 2013;Young et al 2015) have been found to be involved in the genetic regulation of cell-fate and apoptosis as well as in mood and related psychiatric disorders.…”

Behavioral Feeding Circuit: Dietary Fat-Induced Effects of Inflammatory Mediators in the Hypothalamus

“…Prenatal HFD exposure can impact DNA methylation of several genes related to dietary fat intake (62,63) as well as the levels and activity of several transcription factors that have been associated with brain development (64), such as transcriptional enhancer factor-1 (TEF-1), yes-associated protein-1 (YAP-1), and the family of peroxisome proliferatoractivated receptors (PPARs), that in turn effect the expression of some of the orexigenic neuropeptides (65)(66)(67)(68). The transcription factors TEF-1 and YAP-1 has been linked to prenatal HFD effects and plays a large role in organ formation and brain development during embryogenesis (69)(70)(71)(72), and activation of these transcription factors have been found to control neuronal proliferation and differentiation (73)(74)(75). Both TEF-1 and YAP-1 were inactivated or decreased during in utero HFD exposure and may promote increased neurogenesis events (65).…”