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.
Highlights
During neuronal differentiation progenitor cells are instructed according to a precise spatial and temporal plan, and specific signals control the equilibrium between proliferation and differentiation
Our analyses revealed that (1) FOXG1 impaired Transforming growth factor β (TGFβ)-induced neuronal differentiation in early developmental stages, i.e. E13.5; (2) FOXG1 blocks transcription of Cdkn1a, Tgfβ, Foxo1 and Foxo3; (3) expression of Cdkn1a is activated by FOXO1; (4) neither CDKN1A, FOXO1 or FOXO3 can stimulate neuronal differentiation autonomously; and (5) Kcnh3 is a novel neuronal FOXG1-regulated target gene which might be of clinical relevance in atypical Rett syndrome
FOXG1 has the ability to prevent premature differentiation [16] and it antagonizes the TGFβ-pathway by inhibiting Cdkn1a transcription through association with the Forkhead box O (FOXO)/SMAD4 complex, at least in keratinocytes [7]
Summary
During neuronal differentiation progenitor cells are instructed according to a precise spatial and temporal plan, and specific signals control the equilibrium between proliferation and differentiation. Among these signals are extrinsic cues such as growth factors or activators of intracellular signaling pathways. Transforming growth factor β (TGFβ) is an extrinsic cue implicated in neuronal differentiation of cortical progenitor cells (CPCs) [1, 2]. SMAD/cofactor complexes activate or inhibit context-dependent transcription of a variety of target genes, which is apparent through the diversity of processes controlled by TGFβ [4,5,6]
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