The FOXG1/FOXO/SMAD network balances proliferation and differentiation of cortical progenitors and activatesKcnh3expression in mature neurons

Abstract

Transforming growth factor β (TGFβ)-mediated anti-proliferative and differentiating effects promote neuronal differentiation during embryonic central nervous system development. TGFβ downstream signals, composed of activated SMAD2/3, SMAD4 and a FOXO family member, promote the expression of cyclin-dependent kinase inhibitor Cdkn1a. In early CNS development, IGF1/PI3K signaling and the transcription factor FOXG1 inhibit FOXO- and TGFβ-mediated Cdkn1a transcription. FOXG1 prevents cell cycle exit by binding to the SMAD/FOXO-protein complex. In this study we provide further details on the FOXG1/FOXO/SMAD transcription factor network. We identified ligands of the TGFβ- and IGF-family, Foxo1, Foxo3 and Kcnh3 as novel FOXG1-target genes during telencephalic development and showed that FOXG1 interferes with Foxo1 and Tgfβ transcription. Our data specify that FOXO1 activates Cdkn1a transcription. This process is under control of the IGF1-pathway, as Cdkn1a transcription increases when IGF1-signaling is pharmacologically inhibited. However, overexpression of CDKN1A and knockdown of Foxo1 and Foxo3 is not sufficient for neuronal differentiation, which is probably instructed by TGFβ-signaling. In mature neurons, FOXG1 activates transcription of the seizure-related Kcnh3, which might be a FOXG1-target gene involved in the FOXG1 syndrome pathology.

Elevated FOXG1 and SOX2 in glioblastoma enforces neural stem cell identity through transcriptional control of cell cycle and epigenetic regulators

“…Foxo3, which has an established role in NS cell homeostasis and quiescence, emerged as a functionally important transcriptional target of FOXG1/SOX2. This finding is consistent with Foxo3 as a transcriptional target of Foxg1 during telencephalic development (Vezzali et al 2016). FOXO3 activity is also known to be affected by interaction with FOXG1 at the protein level (Seoane et al 2004); FOXG1 therefore exerts a dual inhibition of FOXO3 activity: at the protein-protein level and through transcriptional suppression.…”

“…Transcriptional repression of Foxo3 by FOXG1/SOX2 removes a barrier to astrocyte cell cycle re-entry Foxo3 has an established role in NS cell homeostasis and quiescence (Webb et al 2013), and a recent study suggests that it is directly regulated by Foxg1 (Vezzali et al 2016). Motif analysis within the ChIP-seq peak regions for FOXG1-V5 reveals enrichment for the forkhead box motif as well as HLH, NF1-CTF, and HMG-box motifs.…”

Evolutionary conservation and conversion of Foxg1 function in brain development

“…Foxg1 interacts with FOXO/SMAD (Vezzali et al . ), a complex that activates TGF β and PI3K/Akt signaling, which is involved in controlling proliferation of neuroepithelial cells by the p21Cip1 promoter (Seoane et al . ).…”

“…The mechanisms that underlie the augmented cell proliferation involve the suppression of multiple cell cycle related pathways by Foxg1. Foxg1 interacts with FOXO/SMAD (Vezzali et al 2016), a complex that activates TGFb and PI3K/Akt signaling, which is involved in controlling proliferation of neuroepithelial cells by the p21Cip1 promoter (Seoane et al 2004). Furthermore, haploinsufficiency of Foxg1 exhibit decreased Tbr2positive basal progenitor population that coincides with increased expression of this cell-cycle inhibitor p21 in the progenitor cells (Siegenthaler et al 2008).…”

Knockdown of Foxg1 in supporting cells increases the trans-differentiation of supporting cells into hair cells in the neonatal mouse cochlea

“…Also, their effect on differentiation and the generation of HCs is related to important genes such as Atoh1 and Neurog1 [26][27][28][29][30][31][32][33][34]. Foxg1 (formerly called Bf-1) is one of the forkhead box (FOX) family genes, and it plays an important role in neuron development and has been reported to engage in crosstalk with Wnt, Notch, and TGFβ signaling in the brain and eye [35][36][37][38][39][40][41][42][43]. In the inner ear, Foxg1 is expressed in almost all cell types in the cochlea, saccule, utricle, and canal cristae, and Foxg1null mice have both morphological and histological defects in inner ear development, including shortened cochleae with multiple rows of HCs and the loss of crista neurons and horizontal ampulla [44,45].…”