Signaling to chromatin

Transforming growth factor β (Tgfβ) mediated neurogenesis has been reported to be increased in older (E16.5) embryonic cortical progenitor cells as compared to that in E13.5 and adult spheres (Vogel et al. 2010). In this project we aimed to reveal key genes that highlight the functions of Tgfβ-signaling during cortical and hippocampal development and function, and how Tgfβ affects neurogenesis in an age-dependent manner.

Consistent with an important role in the establishment and function of neuronal hippocampal networks, our work further highlighted that Tgfβ-signaling is also implicated in controlling expression of enzymes affecting DNA methylation. By bridging altered neuronal activity in response to stress we here established a link between signaling, epigenetics and depression (Grassi et al. 2017).

We investigated the cross-talk and mutually exclusive signals of the PI3K-, mTorc- and Tgfβ-pathways which are implicated to balance proliferation and differentiation in the developing cerebral cortex (Wahane et al. 2014). We further showed that in early cortical 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 and interferes with Foxo1 and Tgfβ transcription (Vezzali et al. 2016).

During cortical development, astrocytes are generated once the peak of neurogenesis is exceeded. Astrocytes comprise a heterogeneous population of cells and we showed that both Tgfβ-signaling and FOXG1 expression serve discriminating some populations in the ventral and dorsal telencephalon (Weise et al. 2018).

Neurogenesis and angiogenesis are both processes influenced by the Tgfβ-signalling pathway. To investigate functions of Tgfβ in forebrain development in vivo, we used a Foxg1-cre-expressing mouse line to conditionally knock-out Tgfbr2. Mutant mice displayed severe haemorrhages mostly in the telencephalon and diencephalon beginning around E13.5. The embryos died between E16 to E17, when the entire forebrain is infiltrated with blood cells. Our work revealed that defective Tgfβ-signalling alters the neuronal secretome that impairs proper migration of endothelial cells (Hellbach et al. 2014).

Further reading:

Schulz R, Vogel T, Dressel R, Krieglstein K  (2008) TGF-beta superfamily members, ActivinA and TGF-beta1, induce apoptosis in oligodendrocytes by different pathways. Cell Tissue Res 334: 327-338.

Schulz R, Vogel T, Mashima T, Tsuruo T, Krieglstein K (2009) Involvement of fractin in TGF-beta-induced apoptosis in oligodendroglial progenitor cells. Glia 57(15): 1619-29.