TGF-β1 promotes cerebral cortex radial glia-astrocyte differentiation in vivo

Abstract

The major neural stem cell population in the developing cerebral cortex is composed of the radial glial cells, which generate glial cells and neurons. The mechanisms that modulate the maintenance of the radial glia (RG) stem cell phenotype, or its differentiation, are not yet completely understood. We previously demonstrated that the transforming growth factor-β1 (TGF-β1) promotes RG differentiation into astrocytes in vitro (Glia 2007; 55:1023-33) through activation of multiple canonical and non-canonical signaling pathways (Dev Neurosci 2012; 34:68-81). However, it remains unknown if TGF-β1 acts in RG-astrocyte differentiation in vivo. Here, we addressed the astrogliogenesis induced by TGF-β1 by using the intraventricular in utero injection in vivo approach. We show that injection of TGF-β1 in the lateral ventricles of E14,5 mice embryos resulted in RG fibers disorganization and premature gliogenesis, evidenced by appearance of GFAP positive cells in the cortical wall. These events were followed by decreased numbers of neurons in the cortical plate (CP). Together, we also described that TGF-β1 actions are region-dependent, once RG cells from dorsal region of the cerebral cortex demonstrated to be more responsive to this cytokine compared with RG from lateral cortex either in vitro as well as in vivo. Our work demonstrated that TGF-β1 is a critical cytokine that regulates RG fate decision and differentiation into astrocytes in vitro and in vivo. We also suggest that RG cells are heterogeneous population that acts as distinct targets of TGF-β1 during cerebral cortex development.

Zeb2: A multifunctional regulator of nervous system development

“…In addition to its indispensable role in neural tube formation, conditional knockout studies have demonstrated that Zeb2 is required for normal cerebral development, which may, in part, reflect roles which TGFb superfamily ligands, such as TGFb1 and GDF5, play during cerebral development (Choe et al, 2012;Hegarty et al, 2013;Lu et al, 2005;Mehler, 2002;Stegeman et al, 2013;Stipursky et al, 2014). Indeed, conditional knockout of Zeb2 in dorsal telencephalic cortical progenitors (Emx1 expression domain) resulted in absence of the entire hippocampal formation and corpus callosum in the mutant mice which survived until juvenile age (3-4 weeks old) (Miquelajauregui et al, 2007).…”

Radial Glia cell infection byToxoplasma gondiidisrupts brain microvascular endothelial cell integrity

“…RG cells are the major multipotent neural stem cell population present during the embryonic cerebral cortex development period and originate most of the neuronal and glial cell types found in neural tissue, by activation of multiple signaling pathways (Gotz and Barde, 2005; Kriegstein and Alvarez-Buylla, 2009; Stipursky et al, 2012; Stipursky et al, 2014). Besides its well-known role as neural stem cells, RG have recently been demonstrated to directly control vascular development and blood brain barrier (BBB) formation in the embryonic cerebral cortex (Ma et al, 2013; Errede et al, 2014; Hirota et al, 2015; Siqueira et al, 2017).…”

“…We have previously demonstrated that the gliogenic and neurogenic potential of RG cells during cerebral cortex development is controlled by TGF-β1 signaling pathway activation, both in vitro and in vivo (Stipursky et al, 2012; Stipursky et al, 2014). Neuroepithelial and RG neural progenitors interact with immature endothelial cells, derived from the perineural vascular plexus (PNVP) that surrounds the neural tissue early during the embryonic period.…”

Episodic Prenatal Exposure To Ethanol Affects Postnatal Neurogenesis In The Macaque Dentate Gyrus And Visual Recognition Memory

“…Ethanol affects both FGF2 and PDGF mediated cell proliferation (e.g., Luo and Miller, 1997, 1999). In contrast, the SZ is rich in transforming growth factor (TGF) β1 and its receptors, but the VZ is lacking TGFβ1 and its receptors (Flanders et al, 1991; Miller, 2003; Kandasamy et al, 2011; Stipursky et al, 2014). TGFβ1 has been shown to promote p21 expression and cell cycle exit (Siegenthaler and Miller, 2005).…”